Abstract
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.
Highlights
Cardiovascular diseases (CVD) remain the leading cause of death worldwide, with hypertension being the number one cause of this high mortality (Forouzanfar et al, 2017)
In the context of hypertension, we have previously shown that L-type Ca2+ channels and IP3R are and concomitantly upregulated in an angiotensin-induced hypertension model through a nuclear factor of activated T cells (NFAT)-dependent pathway (Abou-Saleh et al, 2013)
Hypertension is a complex disease that arises from the interaction of multiple genetic, environmental, nutritional, hormonal, and age-related pathological conditions
Summary
Cardiovascular diseases (CVD) remain the leading cause of death worldwide, with hypertension being the number one cause of this high mortality (Forouzanfar et al, 2017). At least half or more of ischemic stroke, hemorrhagic stroke, ischemic heart disease and other CVD such as cardiomyopathy, aortic aneurysms, or peripheral vascular disease are intimately attributed to elevated blood pressure (BP), or hypertension (Forouzanfar et al, 2017) This burden is on the rise, despite all therapeutic advances made in recent years, especially in elderly people (Gates et al, 2009; GBD 2013 Risk Factors Collaborators et al, 2015; Harvey et al, 2015; GBD 2015 Risk Factors Collaborators, 2016; Thijssen et al, 2016)
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