Underdeveloped bradykinin‐dependent vasorelaxation in immature pulmonary arteries from long term hypoxic sheep is not due to loss of cGMP signaling

Abstract

Endothelial dependent relaxation of the pulmonary vasculature is important during the fetal transition to breathing air. Our studies show bradykinin‐mediated relaxation of the pulmonary vasculature is reduced before birth and that postnatal maturation of nitric oxide (NO) cGMP‐mediated signaling pathways is important to this process. Thus, we tested whether cGMP‐mediated vasorelaxation was blunted before birth by performing wire‐myography on pulmonary arteries (PA) isolated from term‐fetal, newborn, and adult sheep exposed to long term high altitude (3,801 m) hypoxia for >;100 days. The efficacy and potency for serotonin‐induced contraction were evaluated following YC1 activation of soluble guanylate cyclase (sGC) or when cGMP degradation was inhibited with the type 5 phosphodiesterase (PDE5) blocker sildenafil. YC1 and sildenafil decreased the potency for serotonin contraction more prominently in vessels from adults as compared to those from immature sheep. Yet, these drugs reduced the efficacy similarly in nearly all groups, with the exception of adult sheep where YC1 failed to alter the maximum contraction. Overall, sGC and PDE5 dependent cGMP signaling pathways are viable targets for reducing arterial tone and are relevant therapeutic avenues for pulmonary hypertension in newborns and adults. (NSF MRI 0923559, NIH R03HD069746, P01HD031226, R01HD003807, R01HL95973).