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Transient Receptor Potential Vanilloid 4 Channel Mediates Endothelium‐Dependent Vasodilation in Parenchymal Arterioles
Author(s) -
DiazOtero Janice M,
Jackson William F,
Dorrance Anne M
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1015.6
Subject(s) - trpv4 , vasodilation , medicine , endocrinology , electrical impedance myography , transient receptor potential channel , endothelium , vasoconstriction , chemistry , receptor
Chronic hypertension increases the risk of vascular dementia development and damage caused by cerebral ischemia. This may be partially the result of impaired endothelium‐dependent dilation of parenchymal arterioles (PAs) that regulate perfusion of the white matter. Transient receptor potential (TRP) channels such as the TRP vanilloid 4 (TRPV4) regulate endothelium‐dependent vasodilation and calcium homeostasis in peripheral arteries and large cerebral arteries. However, the role of TRPV4 in PA vasodilation has not been studied. We hypothesized that TRPV4 activation is a key regulator of endothelium‐dependent dilation in the PAs from normotensive and hypertensive rats. PAs vasodilation from 14–15 week old male normotensive Sprague Dawley (SD) rats and stroke‐prone spontaneously hypertensive rats (SHRSP) were studied by pressure myography. Data are presented as mean ± SEM. The presence of TRPV4 in the PAs was confirmed by immunostaining. The PAs from SHRSP had increased myogenic tone (30±5 vs 51±6 %tone, n=8; SD vs SHRSP; p = 0.02) and impaired carbachol (CbCh)‐induced dilation (35±7 vs 25±7 %dilation, n=4; SD vs SHRSP; p = 0.001) compared to the SD rats. After the development of myogenic tone (60 mmHg) PAs were incubated with the TRPV4 antagonist, GSK2193874 (GSK2, 10 −7 M) for 10 minutes, then CbCh‐mediated dilation (10 −9 –10 −5 M) was assessed. In normotensive rats, TRPV4 antagonism prevented the CbCh‐induced vasodilation (54±7 vs −7±14 %dilation at 10 −5 M, n = 4; CbCh vs CbCh+GSK2; p =0.008). In the SHRSP, inhibition of TRPV4 caused a loss of myogenic tone in the PAs (46±9 vs 23±12 %tone, n = 4; before vs. after GSK2; p = 0.1) that was not observed in SD rats, but this was not significantly different. TRPV4 antagonism also prevented endothelium‐dependent vasodilation in the PAs from SHRSP (46±1 vs −30±20 %dilation at 10 −5 M, n = 4; CbCh vs CbCh+GSK2; p = 0.02). These data show that TRPV4 plays an important role in mediating endothelium‐dependent dilation in cerebral arterioles from normotensive and hypertensive rats. TRPV4 may also contribute to augmented myogenic tone in SHRSP PAs, a role not observed in PAs from SD rats; this could be due to changes in the expression or activity of TRPV4 in the smooth muscle cells. Our data suggest that TRPV4 may have a critical role in mediating the hypertension‐associated changes in the vascular function of cerebral arterioles. The impaired vasodilation and changes in myogenic tone may compromise the regulation of cerebral blood flow during hypertension. TRPV4 could be a potential therapeutic target to improve vascular function of cerebral arterioles during hypertension and to decrease the risk of stroke and vascular dementia development that accompany hypertension. Support or Funding Information Supported by PO1‐HL070687