title: 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 microM) 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.
authors.affiliation: Clinical Integrative Biology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M5S 1A8, Canada. robert.jankov@sunnybrook.ca
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
authors.forename: Crystal
authors.initials: C
authors.lastname: Kantores
authors.forename: Rosetta
authors.initials: R
authors.lastname: Belcastro
authors.forename: Man
authors.initials: M
authors.lastname: Yi
authors.forename: A Keith
authors.initials: AK
authors.lastname: Tanswell
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000502:physiology*; D005260:Female; D006976:Hypertension, Pulmonary / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D009130:Muscle, Smooth / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019332:Endothelin-1; D051034:Inhibitor of Apoptosis Proteins; D010100:Oxygen