Phospholipase C-β3 is dispensable for vascular constriction but indispensable for vascular hyperplasia

Abstract

Angiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-beta (PLC-beta), thereby inducing Ca2+ mobilization as well as the production of reactive oxygen species (ROS). Since contraction is a unique property of contractile VSMCs, signaling cascades related to the proliferation of VSMCs may differ. However, the specific molecular mechanism that controls the contraction or proliferation of VSMCs remains unclear. AngII-induced ROS production, migration, and proliferation were suppressed by inhibiting PLC-beta 3, inositol trisphosphate (IP3) receptor, and NOX or by silencing PLC-beta 3 or NOX1 but not by NOX4. However, pharmacological inhibition or silencing of PLC-beta 3 or NOX did not affect AngII-induced VSMC contraction. Furthermore, the AngII-dependent constriction of mesenteric arteries isolated from PLC-beta 3 triangle SMC, NOX1-/-, NOX4-/- and normal control mice was similar. AngII-induced VSMC contraction and mesenteric artery constriction were blocked by inhibiting the L-type calcium channel Rho-associated kinase 2 (ROCK2) or myosin light chain kinase (MLCK). The activation of ROCK2 and MLCK was significantly induced in PLC-beta 3 triangle SMC mice, whereas the depletion of Ca2+ in the extracellular medium suppressed the AngII-induced activation of ROCK2, MLCK, and vasoconstriction. AngII-induced hypertension was significantly induced in NOX1-/- and PLC-beta 3 triangle SMC mice, whereas LCCA ligation-induced neointima formation was significantly suppressed in NOX1-/- and PLC-beta 3 triangle SMC mice. These results suggest that PLC-beta 3 is essential for vascular hyperplasia through NOX1-mediated ROS production but is nonessential for vascular constriction or blood pressure regulation. Angiotensin II is important in heart health. It makes blood vessels tighten and grow. This study looked at how AngII affects the creation of reactive oxygen species (ROS, molecules that change cell function) in vascular smooth muscle cells (VSMCs, cells in blood vessel walls). The researchers tested how stopping certain cell signals changes ROS creation and cell behaviors like growth and movement. They found that a specific protein, PLC-beta 3, and an enzyme, NOX1, are key in this process. Stopping these molecules could lower ROS levels and change cell growth and movement, important for blood vessel health. Interestingly, these molecules didn't affect blood vessel tightening, also controlled by AngII. This study could help develop new treatments for blood vessel diseases, potentially helping manage conditions like high blood pressure and heart disease.This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.