Ca2+ microdomains in vascular smooth muscle cells: Roles in vascular tone regulation and hypertension

Abstract

Vascular smooth muscle cells (VSMCs) modulate blood pressure by adjusting vascular contractility. Specific families of ion channels that are expressed in VSMCs regulate membrane potential and intracellular Ca²⁺ concentration ([Ca²⁺]_cyt). Subsets of them are known to form molecular complexes with Ca²⁺-sensitive molecules via scaffolding proteins such as caveolin and junctophilin. This enables localized and molecular complex-specific signal transduction to regulate vascular contractility. This intracellular region is referred to as a Ca²⁺ microdomain. When hypertensive stimuli are applied to blood vessels, gene expression of ion channels and scaffold proteins in vascular cells changes dramatically, often leading to membrane depolarization and increased [Ca²⁺]_cyt. As a result, blood vessels undergo functional remodeling characterized by enhanced contractility. In addition, the transcription of inflammatory genes in vascular cells is also upregulated. This induces leukocyte infiltration into the vascular wall and structural remodeling mediated by VSMC proliferation and extracellular matrix remodeling. This functional and structural remodeling perpetuates the hypertensive state, leading to progressive damage to systemic organs. This review summarizes recent findings on the mechanisms by which Ca²⁺ microdomains in VSMCs regulate contractility. In addition, the changes in Ca²⁺ microdomains due to hypertensive stimuli and their contributions to both functional and structural remodeling are summarized.