Myocardial VEGF expression after cardiopulmonary bypass and cardioplegia.
BACKGROUND
Vascular endothelial growth factor (VEGF) is a heparin-binding glycoprotein that plays a critical role in angiogenesis, vascular remodeling, and regulation of vascular tone and permeability. Because myocardial and peripheral edema and systemic hypotension occur frequently after cardiac operations, we examined the effects of cardiopulmonary bypass (CPB) and cardioplegia on gene expressions of VEGF protein and the VEGF tyrosine kinase receptor flk-1 and coronary vascular responses to VEGF.


RESULTS
Pigs (n = 6) were placed on normothermic CPB and hearts were arrested for 1 hour with a hyperkalemic, cold blood cardioplegic solution. Pigs were then separated from CPB and perfused off CPB for an additional 2 hours. Myocardial and skeletal muscle specimens were obtained for Northern analysis of VEGF protein, flk-1 receptor, and basic fibroblast growth factor (bFGF) mRNA before CPB and after 2 hours of reperfusion. Isolated, precontracted coronary arterioles in pre-CPB dilated potently to exogenous VEGF (dilation = 26 +/- 4% of precontraction at 10(-12) mol/L VEGF). Cardioplegia-reperfusion was associated with a 4 +/- 2-fold (P < 0.05 vs pre-CPB) increase in myocardial VEGF protein mRNA, whereas no similar increase was observed in the skeletal muscle. Flk-1 mRNA was increased 6 +/- 3-fold (P < 0.05 vs pre-CPB) after reperfusion, whereas it was unchanged in the skeletal muscle. Relaxations of precontracted coronary arterioles to VEGF were significantly increased (40 +/- 6% at 10(-12) mol/L, P < 0.05 vs pre-CPB) after 2 hours of reperfusion, but those to the endothelium-dependent vasodilator ADP and the endothelium-independent vasodilator nitroprusside were not changed, suggesting that the VEGF receptors remain intact and function is selectively upregulated. In contrast, relaxation responses of microvessels to bFGF were not altered after cardioplegia-reperfusion, and there was no increase in bFGF mRNA in either myocardium or skeletal muscle.


CONCLUSIONS
This study shows that VEGF protein and its flk-1 receptor gene expressions are selectively increased and the potent VEGF-induced vascular responses are enhanced in the coronary microcirculation after blood cardioplegia. The respective parameters are unchanged in the skeletal muscle after normothermic CPB. These findings may have important implications regarding postoperative coronary blood flow regulation, increases in myocardial edema, and vascular remodeling after cardioplegia-reperfusion.
Tofukuji
M
M
Department of Surgery, Beth Israel-Deaconess Medical Center, Boston, MA 02215, USA.
Metais
C
C
Li
J
J
Franklin
A
A
Simons
M
M
Sellke
F W
FW
D000818:Animals; D002315:Cardiopulmonary Bypass; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000494:pharmacology; D006324:Heart Arrest, Induced; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D013552:Swine; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor