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

被引:61
|
作者
Schreier, Barbara [1 ]
Rabe, Sindy
Schneider, Bettina [1 ]
Bretschneider, Maria [1 ]
Rupp, Sebastian
Ruhs, Stefanie
Neumann, Joachim [2 ]
Rueckschloss, Uwe [1 ]
Sibilia, Maria [3 ]
Gotthardt, Michael
Grossmann, Claudia [1 ]
Gekle, Michael
机构
[1] Univ Halle Wittenberg, Julius Bernstein Inst Physiol, Fac Med, D-06112 Halle, Saale, Germany
[2] Univ Halle Wittenberg, Inst Pharmacol & Toxicol, Fac Med, D-06112 Halle, Saale, Germany
[3] Med Univ Vienna, Ctr Comprehens Canc, Dept Med 1, Vienna, Austria
关键词
blood pressure; growth substances; hypertrophy; receptors; smooth muscle; EGF RECEPTOR; MICE LACKING; OXIDATIVE STRESS; NEUREGULIN RECEPTOR; TYROSINE KINASE; EXPRESSION; DELETION; HEART; INHIBITION; PHENOTYPE;
D O I
10.1161/HYPERTENSIONAHA.112.196543
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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 measurements-whereas 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. (Hypertension. 2013;61:333-340.) circle Online Data Supplement
引用
收藏
页码:333 / 340
页数:8
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