Matrix Metalloproteinase 2 as a Potential Mediator of Vascular Smooth Muscle Cell Migration and Chronic Vascular Remodeling in Hypertension

Abstract

For vascular remodeling in hypertension, it is essential that vascular smooth muscle cells (VSMCs) reshape in order to proliferate and migrate. The extracellular matrix (ECM) needs to be degraded to favor VSMC migration. Many proteases, including matrix metalloproteinases (MMPs), contribute to ECM proteolysis and VSMC migration. Bioactive peptides, hemodynamic forces and reactive oxygen-nitrogen species regulate MMP-2 expression and activity. Increased MMP-2 activity contributes to hypertension-induced maladaptive arterial changes and sustained hypertension. New ECM is synthesized to supply VSMCs with bioactive mediators, which stimulate hypertrophy. MMP-2 stimulates the interaction of VSMCs with newly formed ECM, which triggers intracellular signaling via integrins to induce a phenotypic switch and persistent migration. VSMCs switch from a contractile to a synthetic phenotype in order to migrate and contribute to vascular remodeling in hypertension. MMPs also disrupt growth factors bound to ECM, thus contributing to their capacity to regulate VSMC migration. This review sheds light on the proteolytic effects of MMP-2 on ECM and non-ECM substrates in the vasculature and how these effects contribute to VSMC migration in hypertension. The inhibition of MMP activity as a therapeutic target may make it possible to reduce arterial maladaptation caused by hypertension and prevent the resulting fatal cardiovascular events.

Fibulin-3 Attenuates Phosphate-Induced Vascular Smooth Muscle Cell Calcification by Inhibition of Oxidative Stress

“…Downstream effectors of oxidative stress in VSMCs include plasminogen activator inhibitor PAI-1 [16, 54] and the matrix metalloproteinases MMP2 and MMP9, also known as gelatinases [14-17, 55]. The increased PAI-1 expression, a regulator of VSMCs calcification [28, 56], is attenuated by Fibulin-3 during high phosphate conditions.…”

“…However, Fibulin-3 reduces systolic blood pressure and improves vascular health [10], at least in part, by reducing aortic oxidative stress [10-12] and expression of matrix gelatinases [10, 13]. In vascular smooth muscle cells (VSMCs), gelatinase expression and activity are stimulated by excessive oxidative stress [14-17]. …”

The hypertension of hemophilia is associated with vascular remodeling in the joint

“…For example, TNF‐β, which is upregulated in joint tissues after hemarthrosis in hemophilic mice, increases the activity of MMP‐2 and other MMPs that are well known to contribute to maladaptive vascular remodeling in hypertension. These enzymes degrade basement membranes, thereby facilitating migration and proliferation of vascular smooth muscle cells. It has been demonstrated that following joint bleeding, MMPs are overexpressed in joints of hemophilic mice, and basement membrane turnover is accelerated in hemophilic rat joints .…”

Matrix Metalloproteases in Arterial Hypertension and their Trend after Antihypertensive Treatment

“…Reciprocal interaction between vascular cells and their ECM is pivotal in blood vessel formation and remodelling [1]. Hypertensive vascular remodelling is an adaptive response to changes in the blood-pressure-induced circumferential wall stress and blood-flow-induced wall shear stress, which result in the degradation and reorganization of the vascular ECM protein, such as collagen, elastin, proteoglycan and fibronectin [2, 3]. …”

“…The renin-angiotensin system plays a pivotal role in vascular remodelling: angiotensin II has some effects on vascular fibroblast proliferation, ECM protein production and adhesion to matrix proteins. The hypertrophic remodelling is associated with an increase in the arterial wall thickness characterized by collagen deposition and elastin degradation, it is also common in large arteries, such as the aorta, in chronic severe hypertension [2]. …”