Ontogeny of vascular growth factors in perinatal sheep myocardium.

Objective: To examine developmental changes in myocardial gene expression of previously identified regulators of vascular growth.

Methods: Ovine left (LV) and right ventricle (RV) samples were obtained at four time points: 95 days' and 140 days' gestation (term = 145 days) and 7 days and 8 weeks postnatally. mRNA and protein levels of vascular endothelial growth factor (VEGF), its respective receptors (Flk-1 and Flt-1), basic fibroblast growth factor (bFGF), transforming growth factor-beta1 (TGF-beta1), and endothelial nitric oxide synthase (eNOS) were measured at these different time points.

Results: RV but not LV VEGF mRNA levels decreased postnatally, although VEGF protein expression remained unchanged after birth. Flt-1 mRNA expression was divergent between ventricles, although the protein expression pattern was similar in RV and LV, decreasing with maturation. RV and LV Flk-1 mRNA decreased between 95 days and 140 days, remaining stable thereafter, while protein levels only decreased after birth. bFGF protein levels were highest in the LV at 140 days, and decreased after birth but remained unchanged in the RV throughout the period examined. TGF-beta1 and eNOS levels were highest early in gestation, decreasing with maturation in both ventricles.

Conclusion: Developmentally regulated ventricle-specific expression of VEGF, Flt-1, Flk-1, TGF-beta1, bFGF, and eNOS was demonstrated in the ovine myocardium. These findings suggest these proteins may participate in coronary vascular remodeling during the perinatal period and underscore the importance of studying the relationships among transcription factors, target genes, and anatomic/physiologic changes in the whole animal.