Role of platelet-activating factor in pulmonary vascular remodeling associated with chronic high altitude hypoxia in ovine fetal lambs

Abstract

Platelet-activating factor (PAF) is implicated in pathogenesis of chronic hypoxia-induced pulmonary hypertension in some animal models and in neonates. Effects of chronic hypoxia on PAF receptor (PAF-R) system in fetal pulmonary vasculature are unknown. We investigated the effect of chronic high altitude hypoxia (HAH) in fetal lambs [pregnant ewes were kept at 3,801 m (12,470 ft) altitude from approximately 35 to 145 days gestation] on PAF-R-mediated effects in the pulmonary vasculature. Age-matched controls were kept at sea level. Intrapulmonary arteries were isolated, and smooth muscle cells (SMC-PA) were cultured from HAH and control fetuses. To determine presence of pulmonary vascular remodeling, lung tissue sections were subjected to morphometric analysis. Percentage medial wall thickness was significantly increased (P < 0.05) in arteries at all levels in the HAH lambs. PAF-R protein expression studied by immunocytochemistry and Western blot analysis on lung tissue SMC-PA demonstrated greater PAF-R expression in HAH lambs. PAF-R binding (femtomoles per 10(6) cells) in HAH SMC-PA was 90.3 +/- 4.08 and 66% greater than 54.3 +/- 4.9 in control SMC-PA. Pulmonary arteries from HAH fetuses synthesized >3-fold PAF than vessels from controls. Compared with controls SMC-PA of HAH lambs demonstrated 139% and 40% greater proliferation in 10% FBS alone and with 10 nM PAF, respectively. Our data demonstrate that exposure of ovine fetuses to HAH will result in significant upregulation of PAF synthesis, PAF-R expression, and PAF-R-mediated effects in pulmonary arteries. These findings suggest that increased PAF-R protein expression and increased PAF binding contribute to pulmonary vascular remodeling in these animals and may predispose them to persistent pulmonary hypertension after birth.

Effect of Chronic High Altitude Hypoxia on Foetal and Maternal Juxta-Alveolar Distal Pulmonary Smooth Muscle Cells Actin and Calponin Organisation and Growth Profiles

“…3 Other studies have shown effects of hypoxia on nitric oxide mediated reactivity of intrapulmonary veins and arteries 9,10,11 or on remodeling of intrapulmonary vessels. 12,13 Following the observation of Murata et al, (2001) 1 which suggests a stronger effect of hypoxia on vascular remodeling than on nitric oxide mediated vascular reactivity of intrapulmonary vessels, the present study reveals that pathological changes beyond the intrapulmonary vessels, at the extreme end of the pulmonary or bronchiolar trees and alveolar regions, may also be a major cause of disease induced by chronic hypoxia. …”

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

“…NO acts on nearby smooth muscle cells to cause downstream stimulation of soluble guanylate cyclase (sGC) pathways that leads to vasorelaxation (3,45). Previous studies have shown that regulation of vessel relaxation through various receptor signaling systems is altered during pre-and postnatal development, as well as following prenatal chronic hypoxia, which imposes a significant stress on the fetus (9,10,35). Evidence suggests that acetylcholine (ACh)-dependent endothelium-mediated relaxation of the pulmonary vasculature is reduced in the fetus relative to the adult (57).…”

Cardiovascular Adaptation to High-Altitude Hypoxia

“…These findings suggest that EGFR plays a role in fetal ovine pulmonary vascular remodeling following long-term HAH and that inhibition of EGFR signaling may reverse high altitude-induced pulmonary vascular remodeling. Similar to EGFR, platelet-activating factor (PAF) and PAF receptor have also been implicated in the pathogenesis of long-term HAH-induced pulmonary remodeling and hypertension in different animal models [56,57]. In those studies, high PAF and PAF receptor expression levels in the pulmonary arteries have been reported in the long-term hypoxia-exposed animals [56,57].…”

“…Similar to EGFR, platelet-activating factor (PAF) and PAF receptor have also been implicated in the pathogenesis of long-term HAH-induced pulmonary remodeling and hypertension in different animal models [56,57]. In those studies, high PAF and PAF receptor expression levels in the pulmonary arteries have been reported in the long-term hypoxia-exposed animals [56,57]. Furthermore, PAF receptor antagonists attenuated hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling [56], suggesting that PAF receptor-mediated signaling also plays a key role in pulmonary vascular remodeling.…”