STRETCH-INDUCED VEGF EXPRESSION IN THE HEART

Vascular endothelial growth factor (VEGF) is an endothelial cell mitog en involved in vascular development and angiogenesis. Recently we have observed increased VEGF expression in the normal myocardium after myo cardial infarction in a rat heart. This study was designed to explore the mechanism responsible for this increase in VEGF expression, Induct ion of myocardial stretch in an isolated perfused Langendorff preparat ion by inflation of an intraventricular balloon to an end-diastolic lo ad of 35 mmHg for 30 min resulted in a nearly sixfold increase in VEGF message level not only in the chamber subjected to stretch (left vent ricle) but also in the unstretched right ventricle, thus raising the p ossibility of a soluble factor mediating stretch-induced induction of VEGF expression, This was further confirmed by demonstrating that coro nary venous effluent collected from the stretched heart and used to pe rfuse isolated hearts in which no balloon was present was able to indu ce VEGF expression in these normal hearts. Inhibition of TGF-beta acti vity using a neutralizing antibody, but not antagonists/inhibitors of endothelin and angiotensin II, eliminated stretch-induced increase in VEGF expression. Staurosporine, a protein kinase C inhibitor, also blo cked stretch-induced increase of VEGF expression, Measurement of TGF-b eta concentration in the perfusate demonstrated increased amounts of t he cytokine after myocardial stretch, and addition of TGF-beta protein to the perfusion buffer resulted in increased VEGF expression in cont rol hearts, These results suggest that stretch-induced increase of VEG F expression in the heart is mediated at least in part by TGF-beta.