Activation of Neuronal Transient Receptor Potential Vanilloid 1 Channel Underlies 20-Hydroxyeicosatetraenoic Acid–Induced Vasoactivity

Abstract

Abstract-A rise in intraluminal pressure triggers vasoconstriction in resistance arteries, which is associated with local generation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Importantly, dysregulation of 20-HETE synthesis and activity has been implicated in several cardiovascular disease states, including ischemic disease, hypertension, and stroke; however, the exact molecular pathways involved in mediating 20-HETE bioactivity are uncertain. We investigated whether 20-HETE activates the transient receptor potential vanilloid 1 (TRPV1) and thereby regulates vascular function and blood pressure. We demonstrate that 20-HETE causes dose-dependent increases in blood pressure, coronary perfusion pressure (isolated Langendorff), and pressure-induced constriction of resistance arteries (perfusion myography) that is substantially attenuated in TRPV1 knockout mice and by treatment with the neurokinin 1 receptor antagonist RP67580. Furthermore, we show that both channel activation (via patch-clamping of dorsal root ganglion neurons) and vessel constriction are enhanced under inflammatory conditions, and our findings indicate a predominant role for protein kinase A-mediated sensitization of TRPV1 in these phenomena. Finally, we identify a prominence of these pathway in males compared with females, an effect we relate to reduced protein kinase A-induced phosphorylation of TRPV1. 20-HETE-induced activation of TRPV1, in part, mediates pressure-induced myogenic constriction and underlies 20-HETE-induced elevations in blood pressure and coronary resistance.

Transient Receptor Potential Vanilloid-1 Channels Contribute to the Regulation of Acid- and Base-Induced Vasomotor Responses

“…For example, in response to CAP, vasodilation was shown in rat skin [17] and mesenteric arteries [39], but vasoconstriction was seen in other vessels, e.g., rat skeletal muscle [17,40] or dog mesenteric and renal arteries [41]. Similar vasomotor effects were also found with endogenous TRPV1 agonists, such as the arachidonic acid metabolites anandamide and 20-hydroxyeicosatetraenoic acid [42,43]. Besides the ligand agonists, the involvement of the TRPV1 channel has also been shown in the mediation of heat-induced vascular responses [20,21].…”

20-HETE in the regulation of vascular and cardiac function

“…Scotland et al (Scotland et al, 2004) showed that myogenic response to intraluminal transmural pressure or constriction to 20-HETE in mesenteric small arteries is markedly suppressed following ablation of sensory C-fiber activity or capsazepine (TRPV1 blocker); they further suggested that elevation of intraluminal pressure stimulates generation of 20-HETE which, in turn, activates TRPV1 on C-fiber nerve endings resulting in depolarization of nerves and consequent vasoactive neuropeptide release. Bubb et al (2013) demonstrated that 20-HETE causes dose-dependent increases in blood pressure, coronary perfusion pressure (isolated Langendorff), and pressure-induced constriction of resistance arteries (perfusion myography) that is substantially attenuated in TRPV1 knockout mice. These authors suggested the presence of a vasoconstrictor 20-HETE/TRPV1 pathway that may offer potential for therapeutic targeting in conditions such as hypertension (Bubb et al, 2013).…”

“…Bubb et al (2013) demonstrated that 20-HETE causes dose-dependent increases in blood pressure, coronary perfusion pressure (isolated Langendorff), and pressure-induced constriction of resistance arteries (perfusion myography) that is substantially attenuated in TRPV1 knockout mice. These authors suggested the presence of a vasoconstrictor 20-HETE/TRPV1 pathway that may offer potential for therapeutic targeting in conditions such as hypertension (Bubb et al, 2013). …”

Chemical synthesis and biological evaluation of ω-hydroxy polyunsaturated fatty acids

“…20-HETE has been shown to have detrimental effects in several diseases such as hypertension, 8 cancer, 9 and cardiovascular and kidney diseases, 10 despite its low in vivo concentrations due to reincorporation into membrane phospholipid pools, and plasma protein binding similar to other fatty acids. 1 In addition, significantly increased 20-HETE resulting from chronic administration of rofecoxib to mice suggests that it may contribute to the cardiovascular risks associated with coxibs and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs).…”