Abstract 1481: Angiogenesis, But Not Vasculogenesis, Plays Major Role In Placental Growth Factor (PlGF) Mediated Improvement Of Cardiac Function After Myocardial Infarction
Background: PlGF, a member of VEGF family, beneficially stimulates wound healing process after ischemic tissue injury. We previously reported that PlGF is rapidly produced within infarct myocardium, and the plasma level of PlGF in patients with acute myocardial infarction (MI) is positively correlated with number of monocytes and CD34-positive cells as well as improvement of cardiac function. However, it remains unclear how PlGF promotes healing process after MI.
Methods and Results: Using C57BL/6 mice, recombinant human PlGF (rhPlGF) (10 μg) was infused into the peritoneal cavity for 48 hours after MI. 28-day survival rate was significantly improved (rhPlGF 70.0%, PBS 33.3% p<0.05). Cardiac function was also improved by rhPlGF administration (Left ventricular diastolic diameter; rhPlGF 4.50±0.46mm, PBS 5.14±0.38mm p<0.01, Ejection fraction; rhPlGF 40.6+9.17%, PBS 25.7+7.23% p<0.01). In infarct area, both CD31-positive vascular endothelial cells (rhPlGF 644.6+90.54/mm2, PBS 459.0+73.89/ mm2 p<0.01) and α-smooth muscle actin-positive vessels (rhPlGF 31.6+7.20/mm2, PBS 23.5+7.41/mm2 p<0.01) were increased in rhPlGF-treated group. Next, we examined whether bone marrow derived cells (BMCs) participate the angiogenesis or arteriogenesis. Endothelial progenitor cells (Flk-1+Sca-1+ cells) were mobilized by rhPlGF in peripheral circulation (PBS 1.79+0.68%, rhPlGF 3.1+2.1% p<0.01). Furthermore, rhPlGF promoted the recruitment of GFP-labeled BMCs to the infarcted area (rhPlGF 48.22+11.86/Field, PBS 34.9+5.15/Field p<0.01). But only a few migrated BMCs differentiated into endothelial cells (CD31 and GFP-double positive cells) (rhPlGF 0.76+0.86/Field, PBS 0.40+0.27/Field p=0.24). RT-PCR revealed that the migrated monocytes in infarcted area produced more arteriogenic factors in rhPlGF group (Angiopoietin1/Angiopoietin2; rhPlGF 3.8+2.1, PBS 1.1+0.6 p<0.05) than of control group.
Conclusion: rhPlGF-treatment improved survival and cardiac function of ischemic heart through the recruitment of BMCs to peripheral circulation and injured myocardium. Recruited BMCs stimulated new blood vessels formation by mainly producing local angiogenic factors, but not by self-transdifferentiation into blood vessels.