TGF-β suppresses the upregulation of MMP-2 by vascular smooth muscle cells in response to PDGF-BB

Abstract

During platelet-derived growth factor (PDGF)-BB-mediated recruitment to neovascular sprouts, vascular smooth muscle cells (VSMCs) dedifferentiate from a contractile to a migratory phenotype. This involves the downregulation of contractile markers such as smooth muscle (SM) alpha-actin and the upregulation of promigration genes such as matrix metalloproteinase (MMP)-2. The regulation of MMP-2 in response to PDGF-BB is complex and involves both stimulatory and inhibitory signaling pathways, resulting in a significant delay in upregulation. Here, we provide evidence that the delay in MMP-2 upregulation may be due to the autocrine expression and activation of transforming growth factor (TGF)-beta, which is known to promote the contractile phenotype in VSMCs. Whereas PDGF-BB could induce the loss of stress fibers and focal adhesions, TGF-beta was able to block or reverse this transition to a noncontractile state. TGF-beta did not, however, suppress early signaling events stimulated by PDGF-BB. Over time, though PDGF-BB induced increased TGF-beta1 levels, it suppressed TGF-beta2 and TGF-beta3 expression, leading to a net decrease in the total TGF-beta pool, resulting in the upregulation of MMP-2. Together, these findings indicate that MMP-2 expression is suppressed by a threshold level of active TGF-beta, which in turn promotes a contractile VSMC phenotype that prevents the upregulation of MMP-2.

Matrix metalloproteinases and their inhibitors in pulmonary hypertension

“…Exposure of cultured SMCs to pro-inflammatory molecules like interleukin (IL)-1a, tumour necrosis factor (TNF)-a, and oxidised low-density protein are shown to significantly increase the expression and activity of MT1-MMPs, which further leads to the increased activation of proMMP-2 [43]. However, another study demonstrated that autocrine expression and activation of transforming growth factor (TGF)-b1 antagonises the platelet-derived growth factor (PDGF)-BB (homodimer of PDGF subunit B/beta polypeptide)-induced upregulation of MMP-2 in SMCs during phenotypic modulation [48], suggesting TGF-b1 promotes contractile phenotype by modulating MMPs. Cumulatively, these findings illustrate the differential regulation of MMP expression by different growth factors and cytokines.…”

Age-Related Morphometric Characteristics of Remodeling of Arterial Bed of Hind Limbs in White Rats With Experimental Hypercholesterolemia

“…In the vessels there is an excessive deposition of calcium, transition of smooth myocytes from media into intima. Elastin of arteries is thinned that is characterized by fragmentation phenomena under the influence of matrix metalloproteinases and transforming growth factorTGFβ [12,13]. In contrast, the collagen protein synthesis is promoted with the assistance of angiotensin II, which increases the rigidity of collagen itself and vascular wall [14,15].…”

β3GnT8 Regulates Laryngeal Carcinoma Cell Proliferation Via Targeting MMPs/TIMPs and TGF-β1

“…However, MMPs might negatively regulate cancer cell growth by TGF-β1.For example, MMP-2 expression is suppressed by a threshold level of active TGF-β1, which in turn promotes a contractile vascular smooth muscle cells phenotype that prevents the up-regulation of MMP-2 (Risinger et al, 2010). TGF-β1 modulates the mRNA and protein levels of MMPs (MMP-2 and MMP-9) as much as their inhibitors (TIMP-2 and RECK) (Gomes et al, 2012).…”