Endothelin-1 Inhibits Apoptosis of Pulmonary Arterial Smooth Muscle in the Neonatal Rat

Abstract

Vascular wall remodeling in pulmonary hypertension is contributed to by an aberration in the normal balance between proliferation and apoptosis of smooth muscle. We observed that endothelin (ET)-1 is a critical mediator of vascular remodeling in neonatal rats chronically exposed to 60% O 2 , but has no direct proliferative effects on cultured neonatal rat pulmonary artery smooth muscle cells (PASMCs). These findings led us to hypothesize that ET-1 may modulate remodeling by inhibiting apoptosis of smooth muscle. ET-1 (0.1 M) was found to significantly attenuate both Paclitaxel-and serum deprivation-induced PASMC apoptosis, likely through stimulation of the ET A receptor (ET A R). ET-1 also prevented Paclitaxel-induced up-regulation of pro-apoptotic Bax and cleaved (activated) caspase-3. In rat pups exposed from birth to 60% O 2 for 7 d, arterial wall expression of Bax was decreased and expression of both ET A R and anti-apoptotic Bcl-xL were increased. Furthermore, increased numbers of TUNEL-positive cells were evident in the walls of pulmonary arteries from 60% O 2 -exposed animals treated with a combined ET receptor antagonist, SB217242, relative to air-exposed and vehicle-treated groups. Together, these findings suggest that ET-1 mediates remodeling of neonatal rat pulmonary arteries by inhibiting smooth muscle apoptosis. (Pediatr Res 60: 245-251, 2006) P ulmonary hypertension is a frequently observed complication of critically ill newborn infants that causes considerable mortality and long-term morbidity (1). The pathogenesis of pulmonary hypertension is believed to relate to two phenomena that contribute to increased pulmonary arterial resistance and pressure: sustained vasoconstriction and remodeling of resistance arteries. Arterial wall remodeling is contributed to, in major part, by hyperplasia of the medial smooth muscle layer (2). Remodeling increases vascular resistance through luminal encroachment and enhanced contractile potential (3,4), which limits the effectiveness of established vasodilator therapies. Moreover, given that alveolar and vascular development appear to be interdependent processes, pulmonary hypertension in the newborn may also be associated with inhibition of lung growth and alveolar development (5,6). A greater understanding of the mechanisms leading to pulmonary vascular remodeling in the newborn therefore has the potential to greatly improve outcomes.An aberration in the normal balance between proliferation and apoptosis of smooth muscle contributes to vascular remodeling in pulmonary hypertension (7-9). Studies utilizing various endothelin (ET) receptor antagonists have confirmed that the polypeptide, ET-1, is critical to the pathogenesis of vascular remodeling in both adult and newborn (10,11) rodent models of chronic pulmonary hypertension. A major role for ET-1 in pulmonary hypertension of human newborns is also suggested by observational studies (12,13). In addition to being the most potent vasoconstrictor described to date, ET-1 has been reported to directly modul...

Rescue treatment with a Rho-kinase inhibitor normalizes right ventricular function and reverses remodeling in juvenile rats with chronic pulmonary hypertension

“…Fold or fraction change in Assessment of proliferation, apoptosis, and viability of PASMCs. Primary PASMC-enriched cultures (identified by their characteristic hill-and-valley morphology and positive immunostaining for calponin) were obtained from explants of pooled intrapulmonary arteries from day 14 Sprague-Dawley rat pups, as previously reported in detail (22). Cells were passaged by trypsinization using 0.05% (wt/vol) trypsin/EDTA and centrifugation at 300 g for 5 min, followed by reseeding in 96-well plates.…”

“…In the newborn rat, ET-1 functions not only as a potent vasoconstrictor but also as a survival factor for pulmonary artery smooth muscle cells (PASMCs), through its effects on the ET A receptor (22). We therefore hypothesized that any reversing effects of ROCK inhibition on pulmonary arterial (PA) wall remodeling, presumably through enhanced smooth muscle apoptosis, would be accompanied by attenuated ET-1 and/or ET A receptor expression.…”

Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia

“…SMC consistently irrespective of cellular source, as exogenous ET-1 is proproliferative (41) and promigratory (23) and prevents apoptosis (14). Hypoxia increases ET-1 production (35,39).…”

“…ET-1 binds to specific receptors on PASMC to cause an increase in [Ca 2ϩ ] i and vasoconstriction (40). In many pathological states, includ-ing PAH (36), ET-1 production is increased, leading to an increase in vascular tone, smooth muscle cell (SMC) proliferation, migration, and survival (14,23,41).…”

Safety and tolerability of bosentan in the management of pulmonary arterial hypertension

“…Dysregulation of ET-1 signaling can mediate to abnormal growth and apoptosis of endothelial cells, smooth muscle cells, fi broblasts, and pericytes. 5,6 This property makes it a potential node of control in both the vasoconstrictive and proliferative components of PAH pathogenesis. [7][8][9] Its integral role in these processes made ET-1 signaling a therapeutic target for PAH.…”