Sympathetic perivascular nerves mediate remodeling effects of chronic hypoxia in fetal sheep cerebral arteries

Abstract

Hypoxic increases in VEGF contribute to growth of perivascular nerves, which exert potent trophic effects on cerebral arteries. Here we explore the hypothesis that the perivascular sympathetic innervation (PSI) mediates hypoxic changes in the smooth muscle phenotype, structure and function of fetal lamb middle cerebral arteries (MCA). A right superior cervical ganglionectomy (SANX) was performed on exteriorized sheep fetuses of normoxic (N) and hypoxic (H) time‐dated pregnant sheep. Operated fetuses were returned to the womb and their MCA were harvested 14 days later at term. Chronic hypoxia (CH) decreased norepinephrine (NE) content and uptake capacity in MCA but increased contractile responses to transmural adrenergic stimulation at 8 Hz by up to 10‐ fold. CH significantly increased arterial stiffness by 55%. SANX reduced this hypoxic effect by 69%. NE efficacy decreased with hypoxia from 41% to 24% Kmax. SANX increased NE efficacy 39% in N and 61% in H. Similarly, decreases in NE potency with hypoxia were reversed by SANX. Confocal colocalization of myosin heavy chains with α‐actin increased with CH while MLCK‐MLC20 colocalization in H arteries decreased with SANX compared to controls. In conclusion, CH significantly decreases the density but enhances the function of the PSI in fetal MCA. These nerves appear to help mediate effects of hypoxia on fetal MCA structure and function. Supported by PHS# P01‐HD31226.