Abstract
Resistance arteries show accentuated responsiveness to vasoconstrictor agonists in hypertension, and this abnormality relies partly on enhanced Ca(2+) signaling in vascular smooth muscle (VSM). Although inositol 1,4,5-triphosphate receptors (IP3Rs) are abundant in VSM, their role in the molecular remodeling of the Ca(2+) signaling machinery during hypertension has not been addressed. Therefore, we compared IP3R expression and function between mesenteric arteries of normotensive and hypertensive animals. Levels of IP3R transcript and protein were significantly increased in mesenteric arteries of hypertensive animals, and pharmacological inhibition of the IP3R revealed a higher contribution of IP3-dependent Ca(2+) release to vascular contraction in these arteries. Subsequently, we established cultured aortic VSM A7r5 cells as a cellular model that replicates IP3R up-regulation during hypertension by depolarizing the VSM cell membrane. IP3R up-regulation requires Ca(2+) influx through L-type Ca(2+) channels, followed by activation of the calcineurin-NFAT axis, resulting in IP3R transcription. Functionally, IP3R up-regulation in VSM is associated with enhancement and sensitization of IP3-dependent Ca(2+) release, resulting in increased VSM contraction in response to agonist stimulation.
Highlights
The role of the vascular IP3 receptor (IP3R) in hypertension is unknown
Hypertension Is Coupled to Increased Expression of Vascular IP3R—To determine the expression level of vascular IP3R during hypertension, male C57BL/6 mice were infused subcutaneously with angiotensin II (Ang II) (2 ng/g/min, Ang II-infused hypertensive (AHT)) for 2 weeks, resulting in average systolic blood pressure (SBP) values of 109 Ϯ 2, 136 Ϯ 3, and 152 Ϯ 2 mm Hg at 0, 7, and 14 days, respectively (n ϭ 12 each; Fig. 1A)
PE-induced Contractions Are Enhanced in mesenteric arteries (MA) of AHT Mice— To assess the functional significance of IP3R up-regulation in arteries exposed to hypertension, we sought to determine the contribution of IP3-dependent Ca2ϩ release to vascular contractile responses to the vasoconstrictor agonist, PE
Summary
The role of the vascular IP3 receptor (IP3R) in hypertension is unknown. Results: IP3R are up-regulated in vascular smooth muscle (VSM) in hypertension through the calcineurin-NFAT pathway. PLC-IP3-dependent Ca2ϩ release plays an important role in regulating myogenic tone caused by increased intraluminal pressure in isolated arteries [21, 22], and stretch of isolated VSM cells results in enhanced IP3 levels, leading to Ca2ϩ release [23, 24]. PLC inhibition or Ca2ϩ store depletion results in vasodilation or a decreased myogenic response [25,26,27] These findings suggest that the activity of in situ IP3R is influenced by blood pressure and vasoactive agonists impinging on the VSM cells of resistance arteries. IP3R up-regulation could be recapitulated in cultured VSM cells by depolarization-induced activation of the LTCC, leading to induction of the Ca2ϩ-dependent calcineurin-NFAT signaling pathway. Up-regulation of vascular IP3R is poised to contribute to enhanced Ca2ϩ signaling and vasoreactivity during hypertension
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