Upregulation of VEGF-A without angiogenesis in a mouse model of dilated cardiomyopathy caused by mitochondrial dysfunction.
Angiogenesis is implicated in a variety of human pathologies and may also play a role in the progression of heart failure. We have studied the expression of members of the vascular endothelial growth factor (VEGF) and the angiopoietin families and their receptors in mice lacking the mitochondrial transcription factor A. These mice lack functional respiratory chain activity in their myocytes and develop dilated cardiomyopathy (DCM) postnatally. We studied the hearts of the knockout mice by in situ hybridization, Western blotting analysis, and immunohistochemistry. VEGF-A mRNA and protein levels were elevated in the myocardium of the knockouts. Levels of the hypoxia inducible transcription factor 1 alpha (HIF1 alpha) and of glyceraldehyde-3-phosphate dehydrogenase transcripts were also increased, whereas those of angiopoietin-1 and -2 were reduced. Despite the striking upregulation of VEGF-A, there was no increase in capillary density in the knockout hearts. This study suggests that a disturbance in angiogenesis may contribute to the pathogenesis of DCM.
Tham
Emma
E
Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. emma.tham@cmm.ki.se
Wang
Jianming
J
Piehl
Fredrik
F
Weber
Günther
G
D000818:Animals; D015153:Blotting, Western; D002196:Capillaries; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D003331:Coronary Vessels; D004579:Electron Transport / Q000235:genetics; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B
D016228:Endothelial Growth Factors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B