Downregulation of Endothelial Transient Receptor Potential Vanilloid Type 4 Channel and Small-Conductance of Ca ²⁺ -Activated K ⁺ Channels Underpins Impaired Endothelium-Dependent Hyperpolarization in Hypertension

Abstract

V ascular endothelial cells play an important role in the regulation of vascular tone through the release of both vasorelaxing and vasoconstricting factors.1 Apart from the release of vasorelaxant factors such as nitric oxide and prostaglandins, endothelial cells relax the vascular smooth muscle cells through the generation of endothelium-dependent hyperpolarization (EDH). With respect to EDH, there is consensus that the activation of the small-and intermediate-conductance of Ca 2+ -activated K + channels (SK Ca and IK Ca ) located on endothelial cells results in the generation of EDH. [2][3][4][5][6][7][8] In rat mesenteric arteries, the electric transmission of EDH to the adjacent smooth muscle cells via myoendothelial gap junctions (MEGJs) plays a central role in EDH-mediated responses. [9][10][11] Several recent studies have suggested that Ca 2+ influx through endothelial transient receptor potential vanilloid 4 channel (TRPV4), a member of the TRP family of nonselective cation channels, plays a crucial role in EDHmediated hyperpolarization via the downstream activation of SK Ca and IK Ca in specific beds. 12,13 Although the mechanisms through which TRPV4 interact with SK Ca /IK Ca are not well understood, recent studies have suggested that, in specific beds, Ca 2+ influx through TRPV4 directly activates nearby IK Ca and SK Ca at the myoendothelial microdomain signaling sites to generate EDH. 12.13 In rat mesenteric arteries, it has been reported that the relative contribution of EDH in the acetylcholine-induced relaxations decreases as the vessel size increases.14 Although some previous studies reported little or no EDH-mediated relaxations in the superior mesenteric arteries of the rat, 15,16 acetylcholine evoked robust and consistent EDH-mediated Abstract-Endothelium-dependent hyperpolarization (EDH)-mediated responses are impaired in hypertension, but the underlying mechanisms have not yet been determined. (TRPV4) is a prerequisite for the activation of SK Ca /IK Ca in endothelial cells in specific beds. Here, we attempted to determine whether the impairment of EDH in hypertension is attributable to the dysfunction of TRPV4 and S/IK Ca , using isolated superior mesenteric arteries of 20-week-old strokeprone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto (WKY) rats. In the WKY arteries, EDHmediated responses were reduced by a combination of SK Ca /IK Ca blockers (apamin plus TRAM-34; 1-[(2-chlorophenyl) diphenylmethl]-1H-pyrazole) and by the blockade of TRPV4 with the selective antagonist RN-1734 or HC-067047. In the SHRSP arteries, EDH-mediated hyperpolarization and relaxation were significantly impaired when compared with WKY. GSK1016790A, a selective TRPV4 activator, evoked robust hyperpolarization and relaxation in WKY arteries. In contrast, in SHRSP arteries, the GSK1016790A-evoked hyperpolarization was small and relaxation was absent. Hyperpolarization and relaxation to cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine, a selective SK Ca activator, we...

Augmented astrocyte microdomain Ca2+ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

“…TRPV4 channels expressed in the vasculature serve as molecular detectors and transducers of arteriole myogenic responses (e.g., mechanical stress; Kim et al, 2015). Numerous studies support an important role for endothelial TRPV4 channel-mediated arteriole dilation (Bagher et al, 2012;Marrelli, O'Neil, Brown, & Bryan Jr, 2007;Seki et al, 2017;Sonkusare et al, 2012;Zhang & Gutterman, 2011;Zhang, Papadopoulos, & Hamel, 2013;Zou, Leung, & Vanhoutte, 2015). However, in some vascular beds, TRPV4 channel activation can evoke constriction (Saifeddine et al, 2015;Soni, Peixoto-Neves, Matthews, & Adebiyi, 2017;Zhang et al, 2018).…”

Angiotensin II Receptor–Neprilysin Inhibitor Sacubitril/Valsartan Improves Endothelial Dysfunction in Spontaneously Hypertensive Rats

“…Rings (1.2 mm) with intact endothelium were placed in 5‐mL organ chambers filled with 36°C Krebs solution that had been aerated with 93% O 2 to 7% CO 2 (pH 7.4). Isometric contractile responses were recorded, as described . The rings were then allocated to 1 of the following treatments: (1) control, (2) indomethacin (10 −5 mol/L), and (3) indomethacin (10 −5 mol/L) and N ω ‐nitro‐ l ‐arginine (L‐NAME; 10 −4 mol/L).…”

“…In addition to the release of several vasoactive factors, such as nitric oxide (NO) and prostacyclin, vascular endothelial cells regulate arterial tone through the generation of endothelium‐dependent hyperpolarization (EDH) . Although the mechanisms of endothelial dysfunction in hypertension seem to vary, we have demonstrated that the impaired EDH generation accounts for the decreased endothelium‐dependent relaxation of mesenteric arteries of spontaneously hypertensive rats (SHRs), the most commonly used animal model for human essential hypertension . Reduced EDH‐mediated responses have also been reported in the mesenteric arteries of rats with chronic heart failure …”

“…Isometric contractile responses were recorded, as described. [9][10][11][12] The rings were then allocated to 1 of the following treatments: (1) control, (2) indomethacin (10 À5 mol/L), and (3) indomethacin (10 À5 mol/L) and N x -nitro-L-arginine (L-NAME; 10 À4 mol/L). The rings were contracted with phenylephrine (PE; 10 À5 mol/L), and relaxations in response to ACh were determined in a cumulative manner.…”

Signaling Microdomains within the Myoendothelial Junction

“…In stroke prone spontaneously hypertensive rats, TRPV4 and SK channel expression in the EC was significantly reduced compared to its normotensive control. 36 However, acetylcholine induced vasodilation was not different. The mechanism for this is still unclear, but it may be due to compensatory ER calcium release in the rats'…”