Loss of Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells and Cardiomyocytes Causes Arterial Hypotension and Cardiac Hypertrophy

Abstract

Abstract-The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, contributes to parainflammatory dysregulation, possibly causing cardiovascular dysfunction and remodeling. The physiological role of cardiovascular EGFR is not completely understood. To investigate the physiological importance of EGFR in vascular smooth muscle cells and cardiomyocytes, we generated a mouse model with targeted deletion of the EGFR using the SM22 (smooth muscle-specific protein 22) promoter. While the reproduction of knockout animals was not impaired, life span was significantly reduced. Systolic blood pressure was not different between the 2 genotypes-neither in tail cuff nor in intravascular measurementswhereas total peripheral vascular resistance, diastolic blood pressure, and mean blood pressure were reduced. Loss of vascular smooth muscle cell-EGFR results in a dilated vascular phenotype with minor signs of fibrosis and inflammation. Echocardiography, necropsy, and histology revealed a dramatic eccentric cardiac hypertrophy in knockout mice (2.5-fold increase in heart weight), with increased stroke volume and cardiac output as well as left ventricular wall thickness and lumen. Cardiac hypertrophy is accompanied by an increase in cardiomyocyte volume, a strong tendency to cardiac fibrosis and inflammation, as well as enhanced NADPH-oxidase 4 and hypertrophy marker expression. Thus, in cardiomyocytes, EGFR prevents excessive hypertrophic growth through its impact on reactive oxygen species balance, whereas in vascular smooth muscle cells EGFR contributes to the appropriate vascular wall architecture and vessel reactivity, thereby supporting a physiological vascular tone.

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).…”

Surprisingly, traditional purple bamboo salt, unlike other salts does not induce hypertension in rats

“…It means the loss of vessel wall elasticity and the increase of total peripheral resistance, thus inducing hypertension. Also, it induces hypertrophy (Waki et al, 2013;Schreier et al, 2013). It might be suggested that reported anti-inflammatory potential of PBS finally affected reducing blood pressure.…”

Unexpected Cardiac Hypertrophy by Epidermal Growth Factor Receptor Silencing

“…Schreier et al 1 have recently reported a cardiovascular phenotype of mice lacking epidermal growth factor receptor (EGFR) in vascular smooth muscle cells. The mice were created by breeding EGFR flox/flox mice with SM22Cre +/− mice resulting in almost complete deletion of vascular smooth muscle cell EGFR and partial deletion of cardiac EGFR.…”

“…The investigation by Schreier et al 1 is an important step in elucidating the impact of EGFR in cardiac homeostasis and disease. Future experiments attaining greater cardiac-selective deletion of EGFR and inducible silencing of EGFR in adult mice will be appreciated.…”