Arterial Smooth Muscle Proliferative Responses to ET‐1 are Subject to Hypoxic Pre‐conditioning in Term Fetal Lamb Arteries

Abstract

This study explores the hypothesis that the vascular proliferative response to ET-1 is subject to hypoxic pre-conditioning in term fetal arteries. To test this idea, pregnant ewes were maintained at sea level or at an altitude of 3,820 m for the final 110 days of gestation. Endothelium-denuded carotid arteries harvested from full-term fetuses were cultured in serum-starved media with 3, 10 and 30 nM of ET-1 in normoxic (21% O2) and hypoxic (12% O2) chambers for 48 hours. Proliferative responses were quantified as changes in the colocalization of Non-Muscle (NM) and Smooth Muscle (SM) Myosin Heavy Chain with smooth muscle alpha-actin (SMaA). In normoxic fetal arteries cultured under normoxic conditions (FN-N), ET-1 produced a modest concentration-dependent increase in NM-SMaA colocalization and this effect was depressed 65% in arteries cultured under hypoxic conditions (FN-H). In hypoxic fetal arteries cultured under normoxic conditions (FH-N), responses to normoxic culture were not different than observed in the FN-N group. In hypoxic fetal arteries cultured under hypoxic conditions (FH-H), however, responses to ET-1 were attenuated only 22%. Corresponding numbers for SM-SMaA colocalization reflected a 46% depression in FN arteries, but 25% depression in FH arteries. Together, these results demonstrate that hypoxic acclimatization enhances the ability of smooth muscle to regulate contractile protein organization in response to ET-1-induced proliferation, suggesting that hypoxic preconditioning involves intracellular changes in fetal arterial smooth muscle. This work was supported by National Institutes of Health Grants HL-54120, HD-31266, HL-64867, and NS-076945 and the Loma Linda University School of Medicine.