Inositol 1,4,5-trisphosphate receptors in hypertension

Chronic hypertension remains a major cause of global mortality and morbidity. It is a complex disease that is the clinical manifestation of multiple genetic, environmental, nutritional, hormonal, and aging-related disorders. Evidence supports a role for vascular aging in the development of hypertension involving an impairment in endothelial function together with an alteration in vascular smooth muscle cells (VSMCs) calcium homeostasis leading to increased myogenic tone. Changes in free intracellular calcium levels ([Ca²⁺]i) are mediated either by the influx of Ca²⁺ from the extracellular space or release of Ca²⁺ from intracellular stores, mainly the sarcoplasmic reticulum (SR). The influx of extracellular Ca²⁺ occurs primarily through voltage-gated Ca²⁺ channels (VGCCs), store-operated Ca²⁺ channels (SOC), and Ca²⁺ release-activated channels (CRAC), whereas SR-Ca²⁺ release occurs through inositol trisphosphate receptor (IP₃R) and ryanodine receptors (RyRs). IP₃R-mediated SR-Ca²⁺ release, in the form of Ca²⁺ waves, not only contributes to VSMC contraction and regulates VGCC function but is also intimately involved in structural remodeling of resistance arteries in hypertension. This involves a phenotypic switch of VSMCs as well as an alteration of cytoplasmic Ca²⁺ signaling machinery, a phenomena tightly related to the aging process. Several lines of evidence implicate changes in expression/function levels of IP₃R isoforms in the development of hypertension, VSMC phenotypic switch, and vascular aging. The present review discusses the current knowledge of these mechanisms in an integrative approach and further suggests potential new targets for hypertension management and treatment.