Substance-specific importance of EGFR for vascular smooth muscle cells motility in primary culture

Abstract

Besides their importance for the vascular tone, vascular smooth muscle cells (VSMC) also contribute to pathophysiological vessel alterations. Various G-protein coupled receptor ligands involved in vascular dysfunction and remodeling can transactivate the epidermal growth factor receptor (EGFR) of VSMC, yet the importance of EGFR transactivation for the VSMC phenotype is incompletely understood. The aims of this study were (i) to characterize further the importance of the VSMC-EGFR for proliferation, migration and marker gene expression for inflammation, fibrosis and reactive oxygen species (ROS) homeostasis and (ii) to test the hypothesis that vasoactive substances (endothelin-1, phenylephrine, thrombin, vasopressin and ATP) rely differentially on the EGFR with respect to the abovementioned phenotypic alterations. In primary, aortic VSMC from mice without conditional deletion of the EGFR, proliferation, migration, marker gene expression (inflammation, fibrosis and ROS homeostasis) and cell signaling (ERK 1/2, intracellular calcium) were analyzed. VSMC-EGFR loss reduced collective cell migration and single cell migration probability, while no difference between the genotypes in single cell velocity, chemotaxis or marker gene expression could be observed under control conditions. EGF promoted proliferation, collective cell migration, chemokinesis and chemotaxis and leads to a proinflammatory gene expression profile in wildtype but not in knockout VSMC. Comparing the impact of five vasoactive substances (all reported to transactivate EGFR and all leading to an EGFR dependent increase in ERK1/2 phosphorylation), we demonstrate that the importance of EGFR for their action is substance-dependent and most apparent for crowd migration but plays a minor role for gene expression regulation.

Deletion of the EGF receptor in vascular smooth muscle cells prevents chronic angiotensin II‐induced arterial wall stiffening and media thickening

“…Whether or not VSMC‐EGFR is equally important in vivo for other pathogenetic relevant vasoactive substances that transactivate EGFR cannot be terminally concluded. In cultured VSMC, we could show that the importance of EGFR varies depending on the substance applied . Thus, it is conceivable that the in vivo importance of VSMC‐EGFR for other substances differs.…”

“…The mechanistic importance of EGFR for comprehensive AII‐induced signalling has been elaborated in cultured cells during the last years . Delineating the functional relevance of EGFR or even VSMC‐EGFR and its crosstalk with AII in vivo has been challenging.…”

Novel Zinc Finger Transcription Factor ZFP580 Facilitates All-Trans Retinoic Acid -Induced Vascular Smooth Muscle Cells Differentiation by Rarα-Mediated PI3K/Akt and ERK Signaling

“…The identification of membrane-bound receptors and the delineation of their respective signaling pathways have yielded insight into the mechanisms that control VSMC differentiation and growth and have provided molecular targets for therapy of vascular disease [6][7][8]. In recent years, several nuclear receptor binding factors have been shown to regulate VSMC differentiation and growth.…”

“…Vasoactive substances and their receptors, cytokines, growth factors, and cellular signaling molecules have been reported to be involved in the regulation of VSMC differentiation, migration, and proliferation [6][7][8]. Retinoids are derivatives of vitamin A and are involved in a number of biological processes, including vision, embryogenesis, and differentiation of blood, skin, and tumor cells [9].…”

2-Methoxyestradiol causes matrix metalloproteinase 9-mediated transactivation of epidermal growth factor receptor and angiotensin type 1 receptor downregulation in rat aortic smooth muscle cells

“…In addition, GPCRs can activate receptor tyrosine kinases (RTKs) through transactivation that requires activation of metalloproteases (ADAMs/MMPs). However, the downstream actions are specific to agents involved in the induction of response (48,61). Previous studies have shown that ANG II activates EGFR signaling through ADAM17mediated shedding of HB-EFG-like growth factors (31,43).…”