HYPOXIA SELECTIVELY INDUCES PROLIFERATION IN A SPECIFIC SUBPOPULATIONOF SMOOTH-MUSCLE CELLS IN THE BOVINE NEONATAL PULMONARY ARTERIAL MEDIA

Medial thickening of the pulmonary arterial wall, secondary to smooth muscle cell (SMC) hyperplasia, is commonly observed in neonatal hypoxi c pulmonary hypertension. Because recent studies have demonstrated the existence of multiple phenotypically distinct SMC populations within the arterial media, we hypothesized that these SMC subpopulations woul d differ in their proliferative responses to hypoxic pulmonary hyperte nsion and thus contribute in selective ways to the vascular remodeling process. Expression of meta-vinculin, a muscle-specific cytoskeletal protein, has been shown to reliably distinguish two unique SMC subpopu lations within the bovine pulmonary arterial media. Therefore, to asse ss the proliferative responses of phenotypically distinct SMC subpopul ations in the setting of neonatal pulmonary hypertension, we performed double immunofluorescence staining on pulmonary artery cryosections f rom control and hypertensive calves with antibodies against meta-vincu lin and the proliferation-associated nuclear antigen, Ki-67. We found that, although neonatal pulmonary hypertension caused significant incr eases in overall cell replication, proliferation occurred almost exclu sively in one, the meta-vinculin-negative SMC population, but not the other SMC population expressing meta-vinculin. We also examined fetal pulmonary arteries, where proliferative rates were high and meta-vincu lin expression again reliably distinguished two SMC subpopulations. In contrast to the hypertensive neonate, we found in the fetus that the relative proliferative rates of both SMC subpopulations were equal, th us suggesting the existence of different mechanisms controlling prolif eration and expression of cytoskeletal proteins in the fetus and neona te. We conclude that phenotypically distinct SMC populations in the bo vine arterial media exhibit specific and selective proliferative respo nses to neonatal pulmonary hypertension. Distinct SMC subpopulations m ay, thus, contribute in unique ways to vascular homeostasis under both normal and pathologic conditions.