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Citation: Brosolo, G.; Da Porto, A.;Marcante, S.; Picci, A.; Capilupi, F.;Capilupi, P.; Bertin, N.; Vivarelli, C.;Bulfone, L.; Vacca, A.; et al. Omega-3Fatty Acids in Arterial Hypertension:Is There Any Good News? Int. J. Mol.Sci. 2023, 24, 9520. https://doi.org/10.3390/ijms24119520Academic Editor: IlyaNikolaevich MedvedevReceived: 12 May 2023Revised: 28 May 2023Accepted: 29 May 2023Published: 30 May 2023Copyright: © 2023 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). International Journal of Molecular SciencesReviewOmega-3 Fatty Acids in Arterial Hypertension: Is There AnyGood News?Gabriele Brosolo 1,2,*, Andrea Da Porto 1,3 , Stefano Marcante 1, Alessandro Picci 1, Filippo Capilupi 1,Patrizio Capilupi 1, Nicole Bertin 1,4, Cinzia Vivarelli 1, Luca Bulfone 1,2 , Antonio Vacca 1,2 , Cristiana Catena 1,2and Leonardo A. Sechi 1,2,3,4,*1 Department of Medicine, University of Udine, 33100 Udine, Italy; andrea.daporto@uniud.it (A.D.P.);stefanomarcante@outlook.it (S.M.); aless.picci@gmail.com (A.P.); filippocapilupi@gmail.com (F.C.);patrizio.capilupi@gmail.com (P.C.); nicole.bertin@uniud.it (N.B.); cinzia.vivarelli@asufc.sanita.fvg.it (C.V.);luca.bulfone1@gmail.com (L.B.); antonio.vacca94@gmail.com (A.V.); cristiana.catena@uniud.it (C.C.)2 European Hypertension Excellence Center, Clinica Medica, University of Udine, 33100 Udine, Italy3 Diabetes and Metabolism Unit, Clinica Medica, University of Udine, 33100 Udine, Italy4 Thrombosis and Hemostasis Unit, Clinica Medica, University of Udine, 33100 Udine, Italy* Correspondence: gabriele.brosolo@uniud.it (G.B.); sechi@uniud.it (L.A.S.); Tel.: +39-0432-559804 (L.A.S.)Abstract: Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including alpha-linolenic acid (ALA)and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are “essential” fattyacids mainly obtained from diet sources comprising plant oils, marine blue fish, and commerciallyavailable fish oil supplements. Many epidemiological and retrospective studies suggested thatω-3PUFA consumption decreases the risk of cardiovascular disease, but results of early interventiontrials have not consistently confirmed this effect. In recent years, some large-scale randomizedcontrolled trials have shed new light on the potential role of ω-3 PUFAs, particularly high-dose EPA-only formulations, in cardiovascular prevention, making them an attractive tool for the treatmentof “residual” cardiovascular risk. ω-3 PUFAs' beneficial effects on cardiovascular outcomes gofar beyond the reduction in triglyceride levels and are thought to be mediated by their broadlydocumented “pleiotropic” actions, most of which are directed to vascular protection. A considerablenumber of clinical studies and meta-analyses suggest the beneficial effects of ω-3 PUFAs in theregulation of blood pressure in hypertensive and normotensive subjects. These effects occur mostlythrough regulation of the vascular tone that could be mediated by both endothelium-dependent andindependent mechanisms. In this narrative review, we summarize the results of both experimentaland clinical studies that evaluated the effect of ω-3 PUFAs on blood pressure, highlighting themechanisms of their action on the vascular system and their possible impact on hypertension,hypertension-related vascular damage, and, ultimately, cardiovascular outcomes.Keywords: omega-3 polyunsaturated fatty acids (ω-3 PUFAs); hypertension; linoleic acid (LA); alpha-linoleic acid (ALA); eicosapentaenoic acid (EPA); docosahexaenoic acid (DHA); oxylipins; endothelialdysfunction; arterial stiffness; primary prevention; secondary prevention; residual cardiovascular risk1. IntroductionArterial hypertension is the most frequent chronic disease worldwide [1,2], with aprevalence that reaches 35% of the adult population accounting for 9.4 million yearlydeaths [3]. Hypertension is a major modifiable cardiovascular risk factor, increasing the riskof cardiovascular death and morbidity related to chronic invalidating disorders, includingcoronary, cerebrovascular, and peripheral vascular disease, heart failure, and chronickidney disease [4]. Primary hypertension is a complex pathophysiological condition that ischaracterized at the peripheral vascular level by an imbalance between vasoconstrictionand vasodilatation [5]. This imbalance arises from an intricate interplay of genetic andenvironmental factors that include lifestyle and dietary habits [6]. In this regard andInt. J. Mol. Sci. 2023, 24, 9520. https://doi.org/10.3390/ijms24119520 https://www.mdpi.com/journal/ijmshttps://doi.org/10.3390/ijms24119520https://doi.org/10.3390/ijms24119520https://creativecommons.org/https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://www.mdpi.com/journal/ijmshttps://www.mdpi.comhttps://orcid.org/0000-0001-9995-0169https://orcid.org/0000-0003-1657-4888https://orcid.org/0000-0003-0051-7723https://orcid.org/0000-0002-6242-0209https://doi.org/10.3390/ijms24119520https://www.mdpi.com/journal/ijmshttps://www.mdpi.com/article/10.3390/ijms24119520?type=check_update&version=1Int. J. Mol. Sci. 2023, 24, 9520 2 of 21due to their proven ability to reduce blood pressure (BP), lifestyle changes are highlyrecommended in all patients as the first step to treat hypertension [1,2]. Among lifestylerecommendations, dietary interventions play an essential role to the extent that caloricrestriction contributes to weight loss and supplementation with specific food componentsaffects BP regulation.In the last three decades, omega-3 polyunsaturated fatty acids (ω-3 PUFAs) havegained great interest within the research community, since seminal studies [7–10] reporteda surprisingly low incidence of cardiovascular disease in populations, such as Eskimosand Alaskan Natives, traditionally eating high amounts ofω-3 PUFA-rich fatty fish. Later,epidemiological, observational, interventional studies, comprehensive reviews, and meta-analyses were performed with the aim to define the true potential of ω-3 PUFAs forcardiovascular prevention. Moreover, in vitro and in vivo animal and human studies havepaved the way for a better understanding of the cellular and molecular mechanisms ofω-3PUFA-mediated vascular protection. These studies have clearly demonstrated that ω-3PUFAs possess antioxidant, anti-inflammatory, antithrombotic, and endothelium protec-tive properties [11]. In addition, dietary supplementation with high doses ofω-3 PUFAsmodifies plasma lipids concentrations decreasing serum triglyceride and increasing HDL-cholesterol levels [12–15]. Evidence suggests that triglyceride-rich lipoproteins contributeto the “residual lipoprotein attributable risk” that was reported in high-risk patients treatedwith high-dose statins, despite reaching very low LDL-cholesterol levels [16–19]. Despiteinconsistent results of early randomized controlled trials with triglyceride-lowering drugs,subgroup analyses of more recent studies [20–22] and the results of the REDUCE-IT (Re-duction of Cardiovascular Events with Icosapent Ethyl Intervention Trial) [23] showed asignificant cardiovascular benefit of triglyceride-lowering, thus expanding the potentialrole ofω-3 PUFAs for clinical practice. As a result, national and international guidelinesfor cardiovascular prevention currently recommend regular consumption of ω-3 PUFAs aspart of a healthy diet [24–27]. Moreover,ω-3 PUFA-deficient diets have been classified asthe sixth most relevant dietary risk factor, accounting for 1.5 million deaths and 33 milliondisability-adjusted life years worldwide [28].This narrative review aims to provide an update on the current views of the relevanceofω-3 PUFAs in arterial hypertension. For the purpose ofYokoyama, C.;et al. Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derivedsubstrates and products. J. Biol. Chem. 2007, 282, 22254–22266. [CrossRef]40. Goyens, P.L.; Spilker, M.E.; Zock, P.L.; Katan, M.B.; Mensink, R.P. Conversion of alpha-linolenic acid in humans is influenced bythe absolute amounts of alpha-linolenic acid and linoleic acid in the diet and not by their ratio. Am. J. Clin. Nutr. 2006, 84, 44–53.[CrossRef]41. 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Manson, J.E.; Cook, N.R.; Lee, I.M.; Christen, W.; Bassuk, S.S.; Mora, S.; Gibson, H.; Albert, C.M.; Gordon, D.; Copeland, T.; et al.Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N. Engl. J. Med. 2019, 380, 23–32. [CrossRef]169. ASCEND Study Collaborative Group; Murawska, A.; Young, A.; Lay, M.; Chen, F.; Sammons, E.; Waters, E.; Adler, A.; Bodansky,J.; Farmer, A.; et al. Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus. N. Engl. J. Med. 2018, 379, 1540–1550. [CrossRef]Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individualauthor(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury topeople or property resulting from any ideas, methods, instructions or products referred to in the content.https://doi.org/10.1056/NEJMoa1811403https://doi.org/10.1056/NEJMoa1804989Introduction Biochemistry and Cellular Mechanisms of Polyunsaturated Fatty Acids (PUFAs) General Biochemistry and Biologic Sources of PUFAs PUFAs and Cellular Membranes PUFA and Intracellular Signaling PUFAs and Its Metabolites: Role of Oxylipins -3 PUFAs and Blood Pressure Antihypertensive Mechanisms of -3 PUFAs -3 PUFAs and Cardiac Hemodynamics -3 PUFAs and Regulation of Peripheral Vascular Resistance -3 PUFAs and Endothelium-Dependent Regulation of Vascular Tone -3 PUFAs and Endothelium-Independent Regulation of Vascular Tone -3 PUFAs and the Risk of Hypertension Development -3 PUFAs and Hypertension-Related Vascular Damage Arterial Stiffness Atherosclerosis and Plaque Formation Cardiovascular Prevention Studies Early Studies Recent Studies Conclusions Referencesthis review, we systematicallysearched the medical literature in the English language using the PubMed MeSH andthe terms «omega 3», «polyunsaturated fatty acids», «fish fat», «blood pressure», and«arterial hypertension» for extraction. Publications considered were full-text articles withoriginal human or experimental data for the effect of ω-3 PUFAs on BP and its regulatorymechanisms and meta-analyses and reviews on this same subject. G.B. retrieved the articlesthat were reviewed and discussed with C.C. and L.A.S. for subsequent article selection.Article selection was performed according to the quality of evidence of studies that wasestimated following the Grading of Recommendations, Assessment, Development, andEvaluations (GRADE) criteria that are based on the study design, dimension, consistency,and magnitude and dose-dependency of effect [29]. Only studies rated with moderate-to-high GRADE certainty ratings were considered.2. Biochemistry and Cellular Mechanisms of Polyunsaturated Fatty Acids (PUFAs)2.1. General Biochemistry and Biologic Sources of PUFAsThe nomenclature of PUFAs is based on the number of carbons in the molecule (C)and the position of the first double bond relative to the terminal methyl carbon. Omega (ω)indicates the last methyl carbon as opposed to the carboxyl group of the acyl chain, and -6or -3 indicates the position of the first double bond from the last methyl group [30]. PUFAsare categorized into essential and nonessential according to the ability of the human body tosynthesize them de novo. Nonessential PUFAs are those of the ω-7 andω-9 families sincethey can be synthesized directly from endogenous saturated fatty acids. Essential PUFAsinclude the ω-6 and ω-3 families, which cannot be synthesized de novo because mammalslack enzymes to build up double bonds in the fatty acid chain and must necessarily beInt. J. Mol. Sci. 2023, 24, 9520 3 of 21obtained from the diet. The two parents essential PUFAs are linoleic acid (C18:2, LA) thatis particularly abundant in vegetable oils derived from soybean, corn, sunflowers, andrapeseed and alpha-linoleic acid (C18:3, ALA) that is predominantly found in flaxseed,soybean, canola oils, pumpkin seeds and pumpkin seed oil, perilla seed oil, tofu, walnutsand walnut oil, camelina, hempseed, and some algae. Linoleic acid is the precursor ofω-6PUFAs and is converted into arachidonic acid (C20:4, AA) through the action of elongases(which add carbons to the hydrocarbon chain of the fatty acid) and desaturases (whichreplace single bonds with double bonds). Alpha-linoleic acid (C18:3, ALA) is the precursorof long-chain ω-3 PUFAs through elongation and desaturation of its acyl chain, leadingto the formation of eicosapentaenoic acid (C20:5, EPA) which in turn is converted intodocosahexaenoic acid (C22:6, DHA) [31,32] (Figure 1).Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 3 of 22 families since they can be synthesized directly from endogenous saturated fatty acids. Es-sential PUFAs include the ω-6 and ω-3 families, which cannot be synthesized de novo because mammals lack enzymes to build up double bonds in the fatty acid chain and must necessarily be obtained from the diet. The two parents essential PUFAs are linoleic acid (C18:2, LA) that is particularly abundant in vegetable oils derived from soybean, corn, sunflowers, and rapeseed and alpha-linoleic acid (C18:3, ALA) that is predominantly found in flaxseed, soybean, canola oils, pumpkin seeds and pumpkin seed oil, perilla seed oil, tofu, walnuts and walnut oil, camelina, hempseed, and some algae. Linoleic acid is the precursor of ω-6 PUFAs and is converted into arachidonic acid (C20:4, AA) through the action of elongases (which add carbons to the hydrocarbon chain of the fatty acid) and desaturases (which replace single bonds with double bonds). Alpha-linoleic acid (C18:3, ALA) is the precursor of long-chain ω-3 PUFAs through elongation and desaturation of its acyl chain, leading to the formation of eicosapentaenoic acid (C20:5, EPA) which in turn is converted into docosahexaenoic acid (C22:6, DHA) [31,32] (Figure 1). Figure 1. Structure of polyunsaturated fatty acids and their formation from parental molecules. Although humans can endogenously synthesize long-chain ω-3 PUFAs (EPA, DHA) by elongation and desaturation of dietary ALA, it must be emphasized that these reactions in humans are slow and inefficient, so that the production rate of these compounds is very low [33]. The rate of conversion of ALA to EPA and DHA was estimated to be 20% and 10%, respectively, in women, with apparently lower values in men (8% and 10% corre-spondingly) [34–36]. The main source of EPA and DHA is indeed exogenous, mainly de-rived from fatty fish and seafood (mackerel, salmon, trout, seabass, oysters, sardines, and shrimp). A further element of complexity is represented by the fact that ω-3 PUFAs and ω-6 PUFAs both compete for the same enzymatic pathway involving elongases and de-saturases, leading to the transformation of precursors ALA and LA into EPA/DHA and AA, respectively [37,38]. Although ALA is a more affine substrate for desaturases and elongases, some experimental evidence has demonstrated a slower enzymatic metabolism of ω-3 PUFAs as compared to ω-6 PUFAs [39]. Indeed, adequate intake of both ALA and LA is of paramount importance for human health, and the relative dietary proportions of precursor fatty acids (LA, ALA) determine the net rate of conversion to their respective long-chain derivatives [40,41]. Currently, western diets are abundant in ω-6 PUFAs, being found in meats and poultry alongside deep-fried foodstuffs, a characteristic that favors high LA intake, and relatively deficient in ω-3 PUFAs, with ratios of ω-6 PUFAs to ω-3 PUFAs as high as 15:1 to 16.7:1 [42]. Moreover, research suggests that most of the world's population including those who consume fish regularly have a low omega-3 index (O3i). This is defined as the ratio of EPA and DHA to total fatty acids in erythrocyte membranes Figure 1. Structure of polyunsaturated fatty acids and their formation from parental molecules.Although humans can endogenously synthesize long-chainω-3 PUFAs (EPA, DHA)by elongation and desaturation of dietary ALA, it must be emphasized that these reactionsin humans are slow and inefficient, so that the production rate of these compounds isvery low [33]. The rate of conversion of ALA to EPA and DHA was estimated to be 20%and 10%, respectively, in women, with apparently lower values in men (8% and 10%correspondingly) [34–36]. The main source of EPA and DHA is indeed exogenous, mainlyderived from fatty fish and seafood (mackerel, salmon, trout, seabass, oysters, sardines,and shrimp). A further element of complexity is represented by the fact thatω-3 PUFAsandω-6 PUFAs both compete for the same enzymatic pathway involving elongases anddesaturases, leading to the transformation of precursors ALA and LA into EPA/DHA andAA, respectively [37,38]. Although ALA is a more affine substrate for desaturases andelongases, some experimental evidence has demonstrated a slower enzymatic metabolismofω-3 PUFAs as compared toω-6 PUFAs [39]. Indeed, adequate intake of both ALA andLA is of paramount importance for human health, and the relative dietary proportions ofprecursor fatty acids (LA, ALA) determine the net rate of conversion to their respectivelong-chain derivatives [40,41]. Currently, western diets are abundant inω-6 PUFAs, beingfound in meats and poultry alongside deep-fried foodstuffs, a characteristic that favors highLA intake, and relatively deficient inω-3 PUFAs, with ratios ofω-6 PUFAs toω-3 PUFAs ashigh as 15:1 to 16.7:1 [42]. Moreover, research suggests that most of the world's populationincluding those who consume fish regularly have a low omega-3 index (O3i). This isdefined as the ratio of EPA and DHA to total fatty acids in erythrocyte membranes and asa markerof overall ω-3 PUFA status and values below 8% [43,44] have been previouslyvalidated as a risk factor for cardiovascular disease [45].Int. J. Mol. Sci. 2023, 24, 9520 4 of 212.2. PUFAs and Cellular MembranesAs structural components of membrane phospholipids, PUFAs influence membrane prop-erties and modulate cellular function. Fatty acids are quickly incorporated in phospholipids ofplasma, platelets, neutrophils, and red blood cells, whereas enrichment of other tissues takes alonger time. EPA and DHA interact differently with cellular membranes [46–48]. Preclinicaldata show that EPA has a more stable interaction with surrounding saturated fatty acids,contributing to membrane stability and inhibiting lipid oxidation and cholesterol domainformation. DHA is in a curved shape causing conformational changes that increase membranefluidity and form cholesterol domains with reduced antioxidant activity. These peculiaritiesmay at least in part account for the differences in their clinical effects, with EPA seemingly moreefficient in the mitigation of the atherosclerotic process. ω-3 PUFAs accumulate preferentiallyin the cerebral cortex, retina, testes, muscle, and liver, while ω-6 PUFAs are ubiquitous inall tissues. ω-3 PUFAs are incorporated into membrane phospholipids, where they usuallyrepresent less than 10% of the total amount of fatty acids (in a typical western diet: 10–20%AA, 0.5–1% EPA, and 2–4% DHA). Of note, the dietary intake ofω-3 PUFAs can modify thecomposition of cell membranes in a relatively short time (from days to weeks) [49–51].Plasma membranes consist of a mosaic of functional microdomains that facilitateinteractions between resident proteins and lipids [52,53]. The lipid content of cell mem-branes affects the function of cells and intracellular organelles. Incorporation ofω-3 PUFAsinto these membranes modifies membrane fluidity and biophysics, size, and compositionof these microdomains, namely, lipid rafts and caveolae, that modulate protein functionand signaling events. Lipid rafts are small heterogeneous membrane microdomains richin cholesterol, sphingolipids, and saturated acyl chain [53,54] that influence membranefluidity, protein–protein interaction, ion channel kinetics, signaling processes, and mem-brane protein and receptor trafficking. Caveolae represent a specific subtype of lipid raftmacrodomain that forms flask-shaped membrane invaginations rich in proteins that play arole in endocytosis and signal transduction, including the structural protein caveolin-1 andmany signal transduction proteins [55]. ω-3 PUFAs have been shown to increase the sizeand to change the content of cholesterol and sphingolipids of lipid rafts because of theirlow polar affinity with these types of lipids. These changes by modulating signaling eventssuch as activation of G-protein, endothelial nitric oxide synthase (eNOS), tumor necrosisfactor alpha (TNF-alpha), adhesion molecules, and Toll-like receptors (TLR) can contributeto the anti-inflammatory and antiatherosclerotic properties of ω-3 PUFAs [56–58]. Forexample, enrichment of cellular membranes withω-3 PUFAs disrupts dimerization andrecruitment of toll-like receptor-4, which might contribute to anti-inflammatory effectsby down-regulation of nuclear factor-kappa B (NF-κB) activation. On the other hand,the incorporation of ω-3 PUFAs into lipid membranes might modulate a variety of ionchannels [59]. These include certain voltage-gated (Kv) and inwardly rectifying (Kir) K+channels, voltage-gated (Nav) and epithelial (ENaC) Na+ channels, L-type Ca2+ channels,hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, transient receptorpotential (TRP) channels, various connexins, chloride channels, and P2X receptors [59].2.3. PUFA and Intracellular SignalingModulation of physicochemical properties of cellular and organelle membranes is notthe only mechanism through whichω-3 PUFAs exert their physiological effects. ω-3 PUFAsdirectly interact with membrane channels and proteins. For example, direct modulation ofion channels or G-protein-coupled receptor 120 (GPR 120) might contribute to antiarrhyth-mic or anti-inflammatory effects, respectively [60–62]. GPR 120, highly expressed in humanadipocytes and macrophages, has been identified in recent years as the receptor of ω-3PUFAs [63,64] and has been consequently renamed “Free fatty acid receptor 4” (FFAR4).Binding and activation of FFAR4 by ω-3 PUFAs in macrophages and Kupffer cells trigger adownstream signaling cascade leading to the assembly ofω-3PUFA/FFAR4/β-arrestin-2complex, which in turn dissociates the TAK1/TAB1 heterodimer by binding to and inactivat-ing the TAB1 subunit, consequently reducing NF-κB-mediated cyclooxygenase expressionInt. J. Mol. Sci. 2023, 24, 9520 5 of 21and inflammation [62]. Interestingly, in a study of rodents and lipopolysaccharide-primedbone-marrow-derived macrophages, the ω-3PUFA/FFAR4/β-arrestin-2 complex has alsodemonstrated to inhibit NOD-like receptor protein 3 (NLRP3) inflammasome-dependentinflammation [65]. NLRP3 inflammasome has been identified in the last decade as afunctional bridge between inflammation and atherosclerosis [66], and its downregulationresults in decreased levels of interleukin-1β and decreased production of interleukin-6release by macrophages and C-reactive protein by hepatocytes. Moreover, ω-3 PUFAsdirectly regulate gene expression via nuclear receptors and transcription factors, being thenatural ligands of many key nuclear receptors in multiple tissues, including peroxisomeproliferator-activated receptors (PPAR-alpha, -beta, -delta, and -gamma), hepatic nuclearfactors (HNF-4; -alpha and -gamma), retinoid X receptors (RXR), and liver X receptors(alpha and beta) [67–72]. ω-3 PUFAs are transported into the nucleus by cytoplasmic lipid-binding proteins. Sterol regulatory element binding protein-1c (SREBP-1c) is an example ofa transcription factor whose function is altered byω-3 PUFAs, contributing to their effectson lipid metabolism and inflammatory pathways [73,74].2.4. PUFAs and Its Metabolites: Role of OxylipinsA further mechanism of action of ω-3 PUFAs directly involves their metabolites(ω-3 Oxylipins) that in recent years have gathered great research interest. After beingreleased from phospholipids by cytosolic phospholipase A2 (cPLA2), both ω-6 PUFAsand ω-3 PUFAs are oxygenated by different enzymes, such as cyclooxygenase (COX),lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes. This leads to the synthesisof a broad variety of bioactive lipid compounds, many of which take part in the regu-lation of vascular function and exert potent anti-inflammatory effects [75,76]. “Classicoxylipins” are eicosanoids (including prostaglandins, thromboxanes, and leukotrienes)derived from both ω-6 PUFAs and ω-3 PUFAs. ω-6 PUFA AA is the precursor of twotypes of prostaglandins, thromboxanes, and four types of leukotrienes with strong pro-inflammatory, pro-thrombotic, and vasoconstrictive properties [77,78]. EPA is the precursorof three types of prostaglandins and five types of leukotrienes [38] that are 10- to 100-foldless biologically active than their counterparts that are derived from AA and are antag-onistic with their effects on vascular tone, platelet aggregation, and inflammation [77].In this context, when balancing of enzymatic conversions favors 3-series thromboxanes(TXA3 vs. TXA2) and prostacyclines (PGI3 vs. PGI2), the effects of PGI prevail becauseof the relative power of these molecules. In vitro and in vivo experiments show that AAmetabolizing P450-enzymes can use EPA and DHA as alternative substrates. Therefore,EPA/DHA supplementation shifts the P450-eicosanoid profile to EPA- and DHA-derivedepoxy- and hydroxy-metabolites (17,18-epoxy-EPA and 19,20-epoxy-DHA) that are com-monly identified as CYP eicosanoids [79]. These eicosanoids show protective vasoactiveactions and antiarrhythmic properties in cardiomyocytes and are linked to thedevelopmentof hypertension, myocardial infarction, pathological cardiac hypertrophy, stroke, kidneyinjury, and other inflammatory disorders [79,80]. Besides “classic oxylipins”, ω-3 PU-FAs can generate some other oxylipins, designated “specialized pro-resolving mediators”(SPM), that participate in the resolution of inflammation and exert protective and beneficialeffects on a variety of inflammatory diseases [81,82]. These compounds include resolvins,protectins, and maresins. EPA generates E-series resolvins (RvE1, RvE2, and RvE3) throughthe action of COX, while D-series resolvins (RvD1-D6), protectins, and maresins (includingMaR1 and MaR2) are derived from DHA, through the actions of LOX [81]. Moreover, someω-3 oxylipins, including protectin DX, maresin 1, and resolvin D1, display antioxidantcapacity by regulating the expression of antioxidant proteins including catalase, superoxidedismutase, and glutathione peroxidase activity and attenuating lipid peroxidation andO2-generation [83,84].In summary, the incorporation ofω-3 PUFAs in membrane phospholipids improvesmembrane fluidity and biophysical properties by changing lipid rafts and caveolae char-acteristics, thereby leading to modulation of protein–protein interaction and ion channelInt. J. Mol. Sci. 2023, 24, 9520 6 of 21kinetics. These membrane changes involve also intracellular organelles and trigger a multi-plicity of intracellular signaling mechanisms that can contribute to the antiatheroscleroticproperties ofω-3 PUFAs and to the regulation of peripheral vascular tone (Figure 2).Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 6 of 22 [81]. Moreover, some ῳ-3 oxylipins, including protectin DX, maresin 1, and resolvin D1, display antioxidant capacity by regulating the expression of antioxidant proteins includ-ing catalase, superoxide dismutase, and glutathione peroxidase activity and attenuating lipid peroxidation and O2-generation [83,84]. In summary, the incorporation of ω-3 PUFAs in membrane phospholipids improves membrane fluidity and biophysical properties by changing lipid rafts and caveolae char-acteristics, thereby leading to modulation of protein–protein interaction and ion channel kinetics. These membrane changes involve also intracellular organelles and trigger a mul-tiplicity of intracellular signaling mechanisms that can contribute to the antiatheroscle-rotic properties of ω-3 PUFAs and to the regulation of peripheral vascular tone (Figure 2). Figure 2. Schematic representation of actions of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on cell membranes and intracellular signaling and their relevance for perivascular adipocytes and vascular cell functions. EEQ, epoxyeicosatetraenoic acid; NADPH, nicotinamide adenine dinucleo-tide; SOD, superoxide dismutase; XO, xanthine oxidase; PVAT, perivascular adipose tissue; ADRF, adventitium-derived relaxing factor; COX, cyclooxygenase; PGI2, prostacyclin; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ADMA, asymmetric dimethylarginine; EET, epoxyeicosa-trienoic acid; endothelium-derived hyperpolarizing factor; BKCa, large-conductance voltage- and calcium-activated potassium channel; TRPV-4, transient receptor potential vanilloid-4; TRPC1/5, transient receptor potential cation. 3. ω-3 PUFAs and Blood Pressure The effect of ω-3 PUFAs on BP has been well characterized in the past three decades across multiple trials, systematic reviews, and meta-analyses, most of which included both hypertensive and normotensive individuals. Overall, meta-analyses have shown that relatively high doses of ω-3 PUFAs, usually more than 3 g/day, lead to small albeit mean-ingful BP reductions, particularly in subjects with untreated hypertension. The first meta-analysis appeared in 1993 and included 17 controlled clinical trials (6 in untreated Figure 2. Schematic representation of actions of omega-3 polyunsaturated fatty acids (ω-3 PUFAs)on cell membranes and intracellular signaling and their relevance for perivascular adipocytes andvascular cell functions. EEQ, epoxyeicosatetraenoic acid; NADPH, nicotinamide adenine dinu-cleotide; SOD, superoxide dismutase; XO, xanthine oxidase; PVAT, perivascular adipose tissue;ADRF, adventitium-derived relaxing factor; COX, cyclooxygenase; PGI2, prostacyclin; NO, nitricoxide; eNOS, endothelial nitric oxide synthase; ADMA, asymmetric dimethylarginine; EET, epoxye-icosatrienoic acid; endothelium-derived hyperpolarizing factor; BKCa, large-conductance voltage-and calcium-activated potassium channel; TRPV-4, transient receptor potential vanilloid-4; TRPC1/5,transient receptor potential cation.3. ω-3 PUFAs and Blood PressureThe effect of ω-3 PUFAs on BP has been well characterized in the past three decadesacross multiple trials, systematic reviews, and meta-analyses, most of which included bothhypertensive and normotensive individuals. Overall, meta-analyses have shown that relativelyhigh doses of ω-3 PUFAs, usually more than 3 g/day, lead to small albeit meaningful BPreductions, particularly in subjects with untreated hypertension. The first meta-analysisappeared in 1993 and included 17 controlled clinical trials (6 in untreated hypertensive subjectswithout any other comorbidity and 11 in normotensives) reporting a reduction in systolic BP(SBP) and diastolic BP (DBP) that was significant only in hypertensives (−5.5 and−3.5 mm Hg,respectively) [85], with a median ω-3 PUFA dose of 5 g/day that was administered for amedian of 8 weeks. Another meta-analysis that included 31 controlled clinical trials with1356 healthy or hypertensive participants confirmed a significant reduction in SBP and DBPonly in hypertensive patients (−3.4 and −2 mm Hg, respectively) who took an averageInt. J. Mol. Sci. 2023, 24, 9520 7 of 21ω-3 PUFA dose of 4.8 g/day in the form of fish or fish oil for 3 to 24 weeks [86]. Anothermeta-analysis included a total of 36 studies, 22 of which had a double-blind design [87]. Fishoil reduced SBP by 2.1 mm Hg and DBP by 1.6 mm Hg with effects that tended to be greaterin hypertensive subjects older than 45 years. Effects ofω-3 PUFAs on BP were the object offurther subsequent meta-analyses [88–92], all showing a small but significant reduction in BPlevels. These results have been recently corroborated by an umbrella meta-analysis [93] thatincluded 10 meta-analyses of 131 studies carried out between 1989 and 2021 withω-3 PUFAsupplements across studies of 2.2 to 6 g/day and duration of exposure from 4 to 29 weeks.This meta-analysis has confirmed thatω-3 PUFA decreases SBP (−1.19 mm Hg; 95% CI:−1.76,−0.62, ppronounced in those with lower baselineω-3 PUFA content [95] (Figure 3).Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 8 of 22 Figure 3. Changes in blood pressure levels as measured by noninvasive ambulatory blood pressure monitoring (ABPM) in hypertensive patients who ate 3 weekly meals of trout rich in polyunsatu-rated fatty acids for 6 months. Changes are represented according to change ( increase;  decrease) in erythrocyte cell membrane polyunsaturated to saturated fatty acid ratio (PUFA/SFA). Only hy-pertensive patients with an increased PUFA/SFA had significant 24-hour and nighttime blood pres-sure reduction (adapted from ref. [93]). * pand antithrombotic factors, and pro-inflammatory and anti-inflammatory cytokines. Un-der healthy conditions, the production of EC-derived mediators with opposite effects isbalanced. However, under pathological conditions, this balance shifts towards vasocon-striction, inflammation, cell proliferation, and thrombosis, turning endothelial cells intopropagators of disease [113]. All the classic cardiovascular risk factors cause endothelialdysfunction with a significant reduction in the production or availability of vasodilators,mainly nitric oxide (NO), and a parallel increase in the production of vasoconstrictors,including endothelin-1, angiotensin II, and thromboxane A2 [114].The function of EC can be indirectly assessed in vivo in humans by stimulatingendothelial NO production with pharmacological or mechanical stimuli (endothelial-dependent vasodilation) and comparing the induced vasodilatory response with thatinduced by an exogenous nitrate donor (endothelial-independent vasodilation) [115]. Thedifference between endothelial-dependent and endothelial-independent vasodilation is pro-portional to the extent of endothelial dysfunction [116] which is an independent predictorof cardiovascular events and mortality [117].Several experimental and human studies have demonstrated thatω-3 PUFAs improvethe endothelial response of both normal and damaged endothelium [118]. In EC, incuba-tion with EPA stimulates the production of NO through the activation of endothelial NOsynthase (eNOS) [119] leading to endothelial-dependent vasodilation of arterioles [119,120].NO production by endothelial cells is also indirectly enhanced by ω-3 PUFAs-inducedreduction in circulating asymmetric dimethylarginine, a potent endogenous inhibitor of theeNOS activity [121]. Another mechanism contributing toω-3 PUFA endothelial-dependentregulation of vascular tone is the reduction in oxidative stress [122]. ω-3 PUFAs reduceoxidative stress by decreasing the activity of nicotinamide adenine dinucleotide phos-phate [122], blocking the xanthine oxidase pathway [123], and activating the antioxidantenzyme superoxide dismutase (SOD) [124].Some ω-3 oxylipins have also demonstrated antioxidant capacity. Protectin DX de-rived from DHA, a known isomer of protectin D1, attenuated hydrogen peroxide (H2O2)-mediated reactive oxygen species production by regulating the expression of antioxidantenzymes including catalase and SOD [83]. Maresin 1/Resolvin D1 also improved SOD andglutathione peroxidase activity and attenuated lipid peroxidation and superoxide anion(O2·−) generation [864. ω-3 PUFAs showed also regenerative properties over the vascularendothelium. These properties are mediated by stimulation of the endothelial progenitorcells, an effect that has been reported in healthy subjects and patients at high cardiovascularrisk [125].4.2.2. ω-3 PUFAs and Endothelium-Independent Regulation of Vascular ToneInsight from human and animal studies indicates that, beyond endothelial NO produc-tion, there are other mechanisms involved inω-3 PUFA-mediated regulation of vasculartone. Evidence obtained in studies on blood vessels isolated from experimental animalsdemonstrates thatω-3 PUFA-mediated vasodilatation occurs even after eNOS inhibitionor endothelial removal [126–128], suggesting a direct effect on smooth muscle vascularcells (SMVCs). Ca2+ homeostasis is the major factor involved in the control of SMVC con-traction, which is enhanced by depolarization and resultant Ca2+ influx and is decreasedby hyperpolarizing K+ efflux. A large body of knowledge exists about the interaction ofω-3 PUFAs with SMVC ion channels, contributing to their vasodilatory properties. Theseinclude inhibition of L-type Ca2+ channels, activation of K+ channels, and activation ofTPRV4 (transient receptor potential cation channel subfamily V member 4) channels. Acti-vation of KATP channels is another attractive potential mechanism forω-3 PUFA-inducedvascular relaxation. Nonetheless, the studies investigating the role of KATP channels inInt. J. Mol. Sci. 2023, 24, 9520 10 of 21ω-3 PUFA-mediated vasodilation are limited [129–132], and the mechanism by which ω-3PUFA might activate KATP channels has not yet been clarified [133–135]. Thus, furtherresearch is still needed to investigate the role of these channels in the regulation of vasculartone and BP and their response toω-3 PUFAs.5. ω-3 PUFAs and the Risk of Hypertension DevelopmentAs stated above, there is experimental evidence indicating a beneficial effect of ω-3PUFAs on BP. This is why some epidemiological studies have addressed the possibilitythat sustainedω-3 PUFA consumption, either as supplements or fishmeal, might reducethe risk of hypertension development. Among the 5394 black and white men and womenwho were followed for 10 years in the National Health and Nutrition Examination Survey-I(NHANES-I), a significant interaction between regular fish consumption and the develop-ment of hypertension (BP ≥ 160/90) was found in black women [136]. The prospective,multicenter Coronary Artery Risk Development in Young Adults (CARDIA) Study [137]examined the association of different foods with the development of hypertension in amultiethnic population. In this study, fish intake, both fresh and processed, was not relatedto incident hypertension. In the Korean Genome Epidemiology Study, the interaction offish consumption and ω-3 PUFA supplementation with the development of the metabolicsyndrome was investigated over a follow-up of 4 years [138]. After controlling for con-founders, the odds ratio for developing the metabolic syndrome in men who ate fish dailyin comparison to men who ate fish less than once a week was 0.43. The same significantassociation was not observed in women. In this study, analysis of the association betweenfish consumption and separate components of the metabolic syndrome did not show anyrelationship with the development of hypertension. To examine the association of ω-3PUFAs with metabolic syndrome in 55 uncomplicated hypertensive patients, we measuredthe fatty acid composition of red blood cell membranes [139]. Prevalence of the metabolicsyndrome was 36% and in patients with metabolic syndrome, the membrane content ofω-3 PUFAs was significantly lower than in patients without the metabolic syndrome.In the cohort of the Physicians Health Study (PHS), 12.279 normotensive men werefollowed for 15 years, and the risk of developing hypertension related to fish and ω-3PUFA consumption was examined [140,141]. Results indicated that incident hypertensionwas independent of fish andω-3 PUFA consumption. The incidence of hypertension wasnot significantly different between men who consumed at least five servings per weekof fish compared with those who did not consume any fish and the lack of associationextended to individual types of fish. A possible association between fish consumption andthe development of hypertension was examined in a meta-analysis of eight observational,prospective studies including 56.204 adults free of cardiovascular disease who were nor-motensive at baseline and were followed from 3 to 20 years [98]. In this meta-analysis, therisk of developing hypertension was not associated with fish consumption, but the studyshowed that higher circulating levels of EPA and DHA were significantly associated with alower risk of incident hypertension. Thus, current data in support of the role of fish orω-3PUFA consumption in the prevention of hypertension are extremely weak, whereas lowerlevels ofω-3 PUFAs are seemingly associated with the presence of the metabolic syndrome.6. ω-3 PUFAs and Hypertension-Related Vascular Damage6.1. Arterial StiffnessArterial stiffening is a progressive process that is associated with aging and is acceler-ated by increased BP and levels of blood lipoproteins that reciprocally interact. Arterialstiffening results from both structural and functional changes to the vascular wall[142].Aging and additional pathological conditions induce extensive anatomical rearrangementwith depletion and fragmentation of elastin fibers and deposition of collagen and matrixmetalloproteins, leading to the expansion of the extracellular matrix. On the other hand,endothelial dysfunction with a reduced release of NO contributes to arterial stiffening byincreasing the tone of vascular smooth muscle cells. In hypertension, arterial stiffening isInt. J. Mol. Sci. 2023, 24, 9520 11 of 21an independent predictor of major cardiovascular events. Many noninvasive methods havebeen used for the assessment of arterial stiffness, and measurement of the carotid-femoralpulse wave velocity (PWV) has become very popular among these methods and is nowconsidered the gold standard. Effects of ω-3 PUFA supplementation on PWV and otherindexes of arterial stiffness were analyzed in a systematic review of 10 trials including 550healthy and hypertensive participants who were randomized toω-3 PUFA doses rangingfrom 0.64 to 3.00 g/day or placebo, for a period of 6 to 105 weeks [143]. Treatment withω-3PUFAs improved significantly arterial stiffness with an effect that was independent of BPchanges. In a randomized, controlled clinical trial on healthy subjects, a high dose of fishoil (6 g/day) improved arterial stiffness more effectively than a low dose (3 g/day) [144].In addition to PWV, other markers of vascular reactivity such as arterial diametersand endothelium-dependent and independent vascular responses are important predic-tors of future major cardiovascular events [145,146]. In 45 uncomplicated patients withhypertension, we measured the content of fatty acids in red blood cell membranes asa marker of dietary intake and the vasodilatory response of the brachial artery to botha nitrate donor compound (endothelium-independent vasodilation) and post-ischemicreactive hyperemia (endothelium-dependent flow-mediated dilation) [147]. The baselinecaliber of the brachial artery was significantly lower and vasodilatory response to nitratewas significantly greater in patients with higher polyunsaturated-to-saturated fatty acidratio (PUFA/SFA), whereas no difference was found in flow-mediated dilation. Moreover,PUFA/SFA was independently and inversely related to brachial artery diameter and di-rectly with vasodilatory response to nitrate suggesting a contribution of ω-3 PUFAs toendothelium-independent vascular reactivity. Thus, several lines of evidence stronglysuggest thatω-3 PUFAs contribute to vascular reactivity and arterial stiffening.6.2. Atherosclerosis and Plaque FormationThe formation of atherosclerotic plaques is anticipated by the thickening of the innerarterial layer (intima-media thickness, IMT) that can readily be measured by ultrasound.In a prospective intervention study, 56 hypertensive patients received intensive nutritionalcounseling and three weekly meals of fish containing high amounts of PUFAs and the carotidartery IMT and the red blood cell membrane fatty acid composition with the calculation of thePUFA/SFA ratio were measured at baseline and after 1 year [148]. At baseline, the membranePUFA/SFA ratio was inversely related to the carotid IMT and at follow-up, PUFA/SFA wasincreased in 45% of patients. Regular consumption of fish meals resulted in a reductionin carotid IMT only in those patients who had an increased PUFA/SFA ratio that was in-dependent of changes in body mass, BP, and plasma lipids. Very similar conclusions werereported in other studies conducted in different patients’ settings [149–151]. ω-3 PUFAs werealso proven to stabilize existing atherosclerotic plaques [152] both in critical [152,153] andnoncritical carotid artery stenosis [154]. This occurs through the thickening of the plaque’sfibrous cup and reduction in intra-plaque inflammation that are coupled with an increase inHDL-cholesterol [139,155,156] and reduction in lipoprotein(a) [15,157] levels. Finally, it hasbeen demonstrated thatω-3 PUFA supplementation improves the vascular benefits of drugs,such as statins and aspirin [157–159].7. Cardiovascular Prevention StudiesDespite several lines of evidence suggesting the existence of multiple beneficial vascu-lar effects ofω-3 PUFAs, results of intervention trials on cardiovascular prevention yieldedinconsistent results. This might be due to important differences in subjects involved, typesof ω-3 PUFA supplements, and doses and duration of exposure. To our knowledge, noclinical outcome study has included only hypertensive patients, and outcome data ofω-3PUFA use in hypertension are extrapolated from cardiovascular prevention studies thatincluded substantial proportions of hypertensive patients.Int. J. Mol. Sci. 2023, 24, 9520 12 of 217.1. Early StudiesThe GISSI (Gruppo Italiano per lo Studio nella Sopravvivenza nell’Infarto Miocardico)-Prevenzione trial included 11,324 patients surviving a recent (less than 3 months) my-ocardial infarction who were randomly assigned to 1 g/day of ω-3 PUFAs, 300 mg/dayvitamin E, bothω-3 PUFA and vitamin D, or related placebo [160]. Hypertensive patientswere 36% of the entire study population. Over a 3.5-year follow-up,ω-3 PUFAs loweredsignificantly (by 10%) the risk of the primary combined cardiovascular endpoint of death,nonfatal myocardial infarction, and stroke. The JELIS (Japan EPA Lipid Intervention Study)was an open-label, primary and secondary prevention trial on 18,645 patients with totalcholesterol of 6.5 mmol/L or greater, 35% of whom had hypertension [161]. Patients wererandomly assigned to receive either 1800 mg of EPA daily with statin or only statin for5 years. LDL-cholesterol levels decreased by 25% in both treatment groups, while patientsin the EPA group had also a significant reduction in triglyceride levels, and only patients inthis group had a significant (by 19%) reduction in the primary composite cardiovascularendpoint. Post-hoc analyses of JELIS showed significant reductions in cardiovascularevents with the use of EPA only in secondary prevention settings [162], with the greatestbenefit obtained in patients with high baseline plasma triglycerides [163]. The GISSI-HeartFailure study was a randomized, double-blind, placebo-controlled, survival study thatenrolled patients with class II–IV heart failure who were randomly assigned to receiveω-3 PUFA 1 g/day or placebo [164]. Hypertensive patients were 55% of the entire studypopulation and patients were followed for a median of 3.9 years. Treatment with ω-3PUFAs decreased overall and cardiovascular mortality and hospital admissions by 2%,indicating a small but significant benefit. The ORIGIN (Outcome Reduction with an InitialGlargine Intervention) trial was a double-blind study with a 2-by-2 factorial design thatrandomly assigned 12,536 patients at high risk for cardiovascular events with impairedfasting glucose or diabetes to receive 1 g/day ofω-3 PUFAs (465 mg of EPA and 375 mg ofDHA) or placebo and to receive either insulin glargine or standard care [165]. Hypertensivepatients were 79% of the studied population, and the primary outcome was death fromcardiovascular causes. In this study, no significant benefits ofω-3 PUFAs were observed.The GISSI Risk and Prevention study was a double-blind, placebo-controlled trial, in which12,513 high-risk patients, 85% of whom had hypertension, were randomly assigned toω-3PUFAs 1 g/day or placebo (olive oil) [166]. Patients were followed for a median of 5 yearsreporting no difference in the primary endpoint that included death, nonfatal myocardialinfarction, and nonfatal stroke.7.2. Recent StudiesResults of early studies could not provide clear-cut conclusions on the potentialbenefits of ω-3 PUFAs in cardiovascular prevention. This could be possibly related tothe widespread use of inadequate doses of ω-3 PUFAs or to the need to have a betterselection of patients who could benefit from supplementation. This is why, in recent years,large-scaleintervention trials have been performed using greater ω-3 PUFA daily dosesand focusing on patients with elevated plasma triglyceride levels.The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Interventiontrial) was a randomized, double-blind, placebo-controlled trial involving 8179 patients withestablished cardiovascular disease or with diabetes, at least one additional cardiovascularrisk factor, and plasma triglyceride levels between 135 and 499 mg/dL [23]. Participantswere randomized to receive a daily dose of 4 g of icosapent ethyl (IPE, a highly purified EPApreparation) or placebo (mineral oil). After 4.9 years of follow-up, patients treated with IPEhad a 25% reduction in the primary endpoint, which was a composite of cardiovascular death,nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.The results of this study indicated thatω-3 PUFAs could be beneficial in reducing residualcardiovascular risk in patients with high plasma triglycerides, provided that these are usedin sufficiently high doses and for the long term. The results of REDUCED-IT prompted theInt. J. Mol. Sci. 2023, 24, 9520 13 of 21European Medicines Agency (EMA) to include IPE among the strategies recommended forcardiovascular prevention.ω-3 PUFAs have been tested also in the setting of primary prevention. The STRENGTH(Long-term Outcomes Study to Assess Statin Residual risk with Epanova in High Cardio-vascular Risk Patients) study was a double-blind, placebo-controlled trial that recruited13,078 high cardiovascular risk patients with hypertriglyceridemia, low levels of HDL-cholesterol, and hypertension [167]. Patients received 4 g/day of EPA-DHA or placebo (cornoil) on top of background statin treatment for an average follow-up of 42 months. No differ-ence in the primary composite cardiovascular endpoint was observed between treatmentgroups. The VITAL (Vitamin D and Omega-3 Trial) was a randomized, placebo-controlledstudy with a 2-by-2 factorial design of vitamin D and marine ω-3 PUFAs (1 g/day) in theprimary prevention of cardiovascular disease and cancer [168]. More than 25,000 partici-pants of both sexes, 49% of whom had hypertension, were followed for 5.3 years duringwhichω-3 PUFAs did not result in a lower incidence of major cardiovascular events. An-other primary prevention study (ASCEND, A Study of Cardiovascular Events in Diabetes)recruited patients with diabetes, 77% of whom had also hypertension [169]. Patients wererandomized to receive 1 g/day of ω-3 PUFAs or olive oil and, in a mean follow-up of7.4 years, the frequency of major cardiovascular events was not different between the twogroups.8. ConclusionsAlthough early studies on the use ofω-3 PUFAs in cardiovascular prevention providedhighly controversial results, findings of recent large-scale, randomized clinical trials havereaffirmed the potential advantages of these fatty acids. High-dose EPA formulations havedemonstrated significant benefits both in secondary and primary cardiovascular preven-tion, an effect that has been ascribed to targeting the “residual” cardiovascular risk linkedto triglyceride-rich lipoproteins. However, the benefits of ω-3 PUFAs might go beyondtriglyceride-lowering, encompassing a broad range of additional “pleiotropic” actions. Theseinclude protection from vascular inflammation and thrombosis, improvement of endothelialfunction, and reduction in BP. In vitro and in vivo animal and human studies suggest thatω-3 PUFAs could improve peripheral resistance to blood flow by affecting both endothelium-dependent and endothelium-independent vascular responses. These vascular responses toω-3 PUFAs might translate into BP reduction and evidence has been obtained across mul-tiple trials, systematic reviews, and meta-analyses. In these studies, daily intake of 3 ormore g/day of ω-3 PUFAs caused significant BP reduction, particularly in subjects withuntreated hypertension. Moreover, by decreasing arterial stiffening, slowing the developmentof atherosclerosis, and increasing arterial plaque stability, supplementation withω-3 PUFAsintervenes favorably and at different stages of hypertension-related arterial damage.Despite these intriguing observations, the available evidence of the benefits of ω-3PUFAs in hypertension has never been considered worthy of specific recommendations tobe included in hypertension guidelines [1,2]. This is because no cardiovascular preventionstudy with the use ofω-3 PUFAs has ever been specifically performed in hypertensive pa-tients. This is why outcome data ofω-3 PUFA’s use in hypertension have been extrapolatedfrom other studies that included subsets of hypertensive patients. While waiting for thenecessary evidence, we suggest that high-dose and long-term ω-3 PUFAs supplementationmight be considered in (a) low-risk patients with grade 1 hypertension who are unwillingto start drug treatment and will implement all interventions on lifestyle correction recom-mended by the guidelines; (b) patients with hypertension who meet the inclusion criteria ofthe REDUCE-IT trial (patients older than 45 years with established cardiovascular diseaseor older than 50 years with diabetes and one or more major cardiovascular risk factorpresenting with a serum triglyceride level of 135 mg/dL or more) [23].Author Contributions: Conceptualization, G.B., A.D.P., C.C. and L.A.S.; methodology G.B., A.D.P.,C.C. and L.A.S.; validation, S.M., A.P., F.C., P.C., N.B., C.V., L.B. and A.V.; investigation, G.B., A.D.P.,S.M., A.P., F.C., P.C. and L.A.S.; resources, C.C. and L.A.S.; data curation, G.B., S.M., A.P., F.C.,Int. J. Mol. Sci. 2023, 24, 9520 14 of 21P.C., N.B., C.V., L.B. and A.V.; writing—original draft preparation, G.B., A.D.P., C.C. and L.A.S.;writing—review and editing, S.M., A.P., F.C., P.C., N.B., C.V., L.B. and A.V. All authors have read andagreed to the published version of the manuscript.Funding: This research was funded by a generous contribution from the PierSilverio NassimbeniFoundation.Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable.Data Availability Statement: Not applicable.Conflicts of Interest: The authors declare no conflict of interest.References1. Williams, B.; Mancia, G.; Spiering, W.; Agabiti Rosei, E.; Azizi, M.; Burnier, M.; Clement, D.L.; Coca, A.; de Simone, G.; Dominiczak,A.; et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur. Heart J. 2018, 39, 3021–3104, Erratum in:Eur. Heart J. 2019, 40, 475. [CrossRef] [PubMed]2. 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