TRPV4 Channel–Regulated Microdomains Define a New Paradigm in Hypertension

HomeCirculationVol. 146, No. 7TRPV4 Channel–Regulated Microdomains Define a New Paradigm in Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTRPV4 Channel–Regulated Microdomains Define a New Paradigm in Hypertension Rhian M. Touyz, MD, PhD Rhian M. TouyzRhian M. Touyz Correspondence to: Rhian M. Touyz, MD, PhD, Research Institute of McGill University Health Centre, McGill University, 1001 Bouevard Decarie, Montreal, QC, Canada. Email E-mail Address: [email protected] https://orcid.org/0000-0003-0670-0887 Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec, Canada. Search for more papers by this author Originally published15 Aug 2022https://doi.org/10.1161/CIRCULATIONAHA.122.060980Circulation. 2022;146:565–568This article is a commentary on the followingNovel Smooth Muscle Ca2+-Signaling Nanodomains in Blood Pressure RegulationThe concept of hypertension as a pathology of disordered intracellular calcium distribution was developed in the 1970s.1 This was a time when there was enormous progress in the understanding of intracellular calcium homeostasis, with the development of new fluorescent calcium indicators.2 These fluoroprobes paved the way for subcellular calcium imaging and tracking of cytosolic calcium transients in vascular smooth muscle cells (VSMCs) in real time and clearly demonstrated that increased intracellular free calcium concentration ([Ca2+]) is the major trigger initiating vascular contraction.3 Controlling [Ca2+] to maintain contraction-dilation and vascular tone involves numerous cell membrane calcium-permeable channels, transporters, and exchangers, together with intracellular systems, including the sarcoplasmic reticulum and calcium-binding proteins.4 VSMCs possess a multitude of calcium channels, including voltage-operated channels, receptor-operated channels, store-operated channels, transient receptor potential cation (TRP) channels, and Ca2+-permeable nonselective cation channels, which act in concert to promote calcium influx, leading to increased [Ca2+]i.4Article, see p 548Perturbations associated with cytosolic calcium handling and increased [Ca2+]i are a hallmark of the vasculopathy of hypertension.5 In experimental models of hypertension and VSMCs from hypertensive patients, activation of L-type voltage-operated channels is increased and sensitivity to calcium channel blockers is greater in hypertensive compared with normotensive people.6 Receptor-operated channels and TRP channels have also been implicated in abnormal calcium handling and vascular dysfunction in hypertension and other cardiovascular diseases.7 The significance and clinical relevance of calcium channel activation are confirmed by the proven clinical success of L-type calcium channel blockers in the management of hypertension. These drugs target L-type CaV1.2 calcium channels, prevent VSMC calcium influx, and dampen procontractile signaling, with consequent decreased vascular contraction, increased vasodilation, and reduced blood pressure.8 These drugs, together with other antihypertensive agents, have revolutionized hypertension treatment.8 However, despite their efficacy, blood pressure is still not optimally controlled in patients with hypertension, with <15% of treated patients worldwide achieving guideline-suggested blood pressure targets.9 Although the reasons for this are multifactorial, there are still major gaps in our understanding of fundamental molecular mechanisms that cause hypertensionIn the current issue of Circulation, Chen et al10 fill some of these gaps through their innovative discoveries that smooth muscle cell (SMC) TRPV4 channels are crucial regulators of vascular function and blood pressure. The TRPV4 channel is a member of the TRP superfamily of cation channels comprising canonical channels (TRPC), vanilloid-related channel (TRPV), melastatin-related channel (TRPM), ankyrin-related channels (TRPA), mucolipin-related channel (TRPML), and polycystin-related channel (TRPP).11,12 All TRP channels are characterized by 6 transmembrane domains (TM1–TM6) and 1 loop located between TM5 and TM6, which defines the cation-permeable pore domain. Unlike most cation channels, TRPs are typically regulated by a variety of different stimuli such as temperature fluctuations; mechanical stress; neurohormonal signals; H+, Ca2+, and Mg2+ ions; and vasoactive agents, including prohypertensive hormones angiotensin II and endothelin-1.11 In the Chen et al study,10 humoral factors, sympathetic activation, and increased intraluminal pressure were shown to variably influence SMC TRPV4 channels with different responses in basal conditions and angiotensin II–induced hypertension.Isoforms of TRPC, TRPV, and TRPM have been identified in the vascular system and are emerging as important regulators of vascular tone and function, particularly TRPC1, TRPC3, TRPC6, TRPC7, TRPV1, TRPV4, and TRPM7.9–12 They have also been linked to pathological conditions associated with endothelial dysfunction, vascular contraction, and arterial remodeling, processes that characterize the vasculopathy of hypertension.12Further developing this notion, Chen and colleagues10 demonstrate that vascular TRPV4 channels are critically involved in the pathophysiology of hypertension. However, this is not a new concept. TRPV4 channels have been studied extensively in endothelial cells in hypertension, with preclinical and clinical studies demonstrating that TRPV4 channels interact physically and functionally with calcium-activated potassium channel 3 (KCa2.3).13,14 This interaction is responsible for the endothelium-derived hyperpolarizing factor response, the major mechanism driving vasodilation in resistance arteries and regulation of blood flow and blood pressure. In addition, activated endothelial TRPV4 channels induce calcium influx, calcium-mediated activation of endothelial nitric oxide (NO) synthase, and production of the potent vasodilator NO.14 In experimental models, downregulation of endothelial cell TRPV4 channels or reduced TRPV4:KCa2.3 interaction causes endothelial dysfunction and hypertension, which are normalized when KCA2.3 is overexpressed13 (Figure). Dysregulated endothelial TRPV4 channels and associated endothelial dysfunction are increasingly being considered important pathophysiological mechanisms underlying hypertension, with growing interest in targeting this system therapeutically. To this end, the small-molecule drugs JNc-440 and JNc-463 have been developed that enhance coupling between TRPV4 channels and KCa2.313 and between TRPV4 channels and endothelial NO synthase,14 respectively. These drugs induce vasodilation and blood pressure lowering in mice.13,14 TRPV4 channels have also been implicated in fibroblast activation and adventitial remodeling in pulmonary hypertension.15Download figureDownload PowerPointFigure. Schematic demonstrating the putative role of TRPV4 channels in endothelial cells and VSMCs in basal conditions and in hypertension. Under physiological conditions, activation of TRPV4 channels promotes vasodilation in endothelial cells by associating with endothelial nitric oxide (NO) synthase (eNOS) and calcium-activated potassium channel 3 (KCa2.3), resulting in increased production of NO and endothelium-derived hyperpolarizing factor (EDHF). In vascular smooth muscle cells (VSMCs), there is a balance between TRPV4 channel–regulated procontractile and vasodilator systems, which maintains vascular tone and regulation of blood pressure. Reduced association between TRPV4 channels and eNOS and KCa2.3 in endothelial cells, increased signaling through α1 adrenergic receptors (ARs), and decreased signaling through bradykinin receptors (BKR) in VSMCs lead to increased vasoconstriction and reduced vasodilation with consequent hypertension. MLC indicates myosin light chain; and PKC, protein kinase C.Although most previous studies have focused on dysregulation of TRPV4 channels in endothelial cells in hypertension, it is now evident that VSMCs are also important. Using inducible TRPV4 SMC−/− mice, Chen et al10 show that TRPV4 SMC channels increase blood pressure in basal conditions and contribute to blood pressure elevation in angiotensin II–induced hypertension. The authors go on to unravel underlying molecular mechanisms and demonstrate subpopulations of differentially regulated TRPV4 channels with opposing actions. Specifically, it is shown that α1 adrenergic receptor (α1AR)–activated TRPV4 channels in SMCs promote vasoconstriction through protein kinase C–dependent pathways and calcium signaling, whereas intraluminal pressure–activated TRPV4 channels in SMCs signal through calcium-activated bradykinin channels to cause vasodilation (Figure). These processes appear to be tightly regulated, physically dissociated, and in close proximity in distinct nanodomains. In situ proximity ligation assay show that TRPV4 channels colocalize with α1ARs and bradykinin channels, but α1ARs and bradykinin channels do not colocalize. The authors define a novel system in which, under resting conditions, the procontractile and vasodilatory systems are in balance and maintain vascular tone and blood pressure, whereas a shift to upregulation of vasoconstrictor-α1AR-TRPV4 channel signaling causes an increase in blood pressure. These phenomena seem to be independent of endothelial cell TRPV4 channels because endothelium denudation did not influence TRPV4-induced sparklet activity.10 The dissociation between the endothelial and VSMC TRPV4 channel systems may relate to different receptor-mediated signaling pathways, with endothelial NO synthase–NO and KCa2.3 channel–endothelium-derived hyperpolarizing factor being important in the endothelium and α1AR–protein kinase C–induced procontractile Ca2+ signaling and ryanodine receptor–Ca2+ spark–activated bradykinin channel signaling being important in VSMCs.Chen et al10 have certainly advanced the field of TRP channels, vascular biology, and blood pressure regulation and have highlighted the importance of VSMC TRPV4 channel dysregulation in hypertension. However, a number of caveats warrant further consideration. First, considering the proven importance of endothelial TRPV4 channel–mediated vasorelaxation as a vasoprotective system,13,14 it is difficult to reconcile the findings in the present study that the endothelium does not seem to influence vascular function or blood pressure when VSMC TRPV4 channel–mediated effects are perturbed. This is especially puzzling considering that angiotensin II infusion has previously been shown to downregulate endothelial cell TRPV4 channels. In the intact system, the endothelium and vascular media are in close communication, and accordingly, unravelling cross-talk between TRPV4 in different cell types and the impact on vascular [Ca2+]i regulation will be important.Second, the relative importance of the distinct nanodomains in hypertension likely depends on the integrated effects of multiple stimuli (mechanical, pressure, humoral, etc). Hence, a deeper understanding of how multiple stimuli differentially regulate nanodomains in intact systems would further elucidate their significance in hypertension.Last, it is proposed that targeting TRPV4 channels in VSMCs to regulate calcium signaling may be an effective strategy to normalize vascular dysfunction and to reduce blood pressure in hypertension. Although this is an interesting concept, it is unclear how the procontractile and vasodilator nanodomains in VSMCs would be specifically and independently targeted.Despite some unanswered questions in the study, the proposed paradigm highlighting a role for TRPV4 channels in the pathophysiology of hypertension through perturbations in differentially regulated signaling pathways localized in spatially distinct subcellular microdomains in VSMCs is novel. Chen et al10 make important contributions in delineating new molecular mechanisms underlying hypertension. This offers new directions in hypertension research and highlights important interplay between opposing signaling pathways that both involve TRPV4 channels. To advance these concepts, it will be important to confirm the findings discussed here in which VSMC TRPV4 is endogenously regulated rather than in genetic models in which TRPV4 channels are knocked out in a SMC-specific manner.Article InformationAcknowledgmentsDr Touyz is supported by grants from the Leducq Foundation, Dr Phil Gold Chair, McGill University, and the European Commission.Sources of FundingNone.Disclosures None.FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 567.Correspondence to: Rhian M. Touyz, MD, PhD, Research Institute of McGill University Health Centre, McGill University, 1001 Bouevard Decarie, Montreal, QC, Canada. 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