Inositol 1,4,5-Trisphosphate (IP3) Receptor Up-regulation in Hypertension Is Associated with Sensitization of Ca2+ Release and Vascular Smooth Muscle Contractility

Background: 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. Conclusion: Up-regulated IP3R in VSM sensitize Ca2+ release and enhance contraction. Significance: Up-regulated vascular IP3R may contribute to vascular resistance in hypertension. Resistance arteries show accentuated responsiveness to vasoconstrictor agonists in hypertension, and this abnormality relies partly on enhanced Ca2+ signaling in vascular smooth muscle (VSM). Although inositol 1,4,5-triphosphate receptors (IP(3)Rs) are abundant in VSM, their role in the molecular remodeling of the Ca2+ 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 Ca2+ 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 Ca2+ influx through L-type Ca2+ 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 Ca2+ release, resulting in increased VSM contraction in response to agonist stimulation.