Consequences of postnatal vascular smooth muscle EGFR deletion on acute angiotensin II action

Abstract

Epi dermal growth factor (EGF) receptor (EGFR) is activated by its canonical ligands and transactivated by various vasoactive substances, e.g. angiotensin II (Ang II). Vascular EGFR has been proposed to be involved in vascular tissue homoeostasis and remodelling. Thus, most studies have focused on its role during long-term vascular changes whereas the relevance for acute regulation of vascular function in vivo and ex vivo is insufficiently understood. To investigate the postnatal role of VSMCs (vascular smooth muscle cells) EGFR in vivo and ex vivo, we generated a mouse model with cell-specific and inducible deletion of VSMC EGFR and studied the effect on basal blood pressure, acute pressure response to, among others, Ang II in vivo as well as ex vivo, cardiovascular tissue homoeostasis and vessel morphometry in male mice. In knockout (KO) animals, systolic, diastolic and mean blood pressures were reduced compared with wild-type (WT). Furthermore, Ang II-induced pressure load was lower in KO animals, as was Ang II-induced force development and extracellular-signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in aortic rings from KO animals. By contrast, we observed no difference in force development during application of serotonin, KCl, endothelin-1 or endothelin-1-induced pressure load in KO animals. In addition, nitric oxide (NO)-mediated vasodilation was not affected. Heart weight (HW) increase and up-regulation of aortic and cardiac expression of Ccl2 (chemoattractant protein-2) and serpinE1 (plasminogen activator inhibitor 1) during the transition from 4- to 10-months of age were prevented by VSMC EGFR KO. We conclude that VSMC EGFR is involved in basal blood pressure homoeostasis and acute pressure response to Ang II, and thereby contributes to maturation-related remodelling.

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

“…EGFR expression in aorta and mesenteric arteries of VSMC‐EGFR‐KO was reduced substantially (Table ) in accordance with published results and as confirmed for mesenteric arteries by immunoblot (Figure I) . Furthermore, AII responsiveness of VSMC with respect to ERK1/2 phosphorylation was significantly reduced when EGFR was blocked or missing (Figure ), confirming earlier results …”

“…These mice showed a reduced blood pressure response upon acute AII infusion, proving that VSMC‐EGFR is involved in acute AII effects in vivo. To exclude confounding effects from the knock out in cardiomyocytes, we generated and described a second mouse model with inducible deletion of the EGFR in VSMC but normal cardiac EGFR expression without cardiac alterations . This study confirmed that VSMC‐EGFR is involved in basal blood pressure homoeostasis, contributes to ageing‐related vascular changes, acute AII blood pressure response and acute vascular AII responsiveness .…”

“…To exclude confounding effects from the knock out in cardiomyocytes, we generated and described a second mouse model with inducible deletion of the EGFR in VSMC but normal cardiac EGFR expression without cardiac alterations . This study confirmed that VSMC‐EGFR is involved in basal blood pressure homoeostasis, contributes to ageing‐related vascular changes, acute AII blood pressure response and acute vascular AII responsiveness . This study investigates the in vivo and ex vivo role of VSMC‐EGFR during chronic AII‐related vascular remodelling and renal end‐organ damage, using this genetic model.…”

“…Recently, it was shown that systemic pharmacological EGFR inhibition can prevent vascular remodelling induced by AII . Data on the importance of EGFR for AII‐induced hypertension are controversial, showing either no contribution or a partial but substantial impact . Eventually, these studies document the implication of EGFR in vascular remodelling preceding end‐organ damage and its importance for reno‐cardiovascular health.…”

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…Distinct cardiac and vascular effects of this receptor system may also be relevant -cardiac hypertrophic outcomes may well reflect effects of EGFR on vascular control and blood pressure (Schreier et al, 2013;Schreier et al, 2016).…”