Apoptosis and Regulation of Bax and Bcl-X Proteins During Human Neonatal Vascular Remodeling

Abstract

Abstract-To verify that apoptosis is one of the possible mechanisms of neonatal vascular remodeling during the transition from fetal to neonatal circulation, we assayed for apoptosis and evaluated the expression of apoptosis-regulatory proteins in umbilical vessel versus ascending aorta, ductus arteriosus (DA) versus adjacent pulmonary artery and aorta, or aorta versus its branching arteries. Twenty-two umbilical cords (UCs), 6 DAs with adjacent aortas and pulmonary arteries, and 4 aortic arches with their branching great arteries were obtained from neonates. Smooth muscle cell (SMC) apoptosis in umbilical vessels was identified in all UCs. The expressions of Bax and Bcl-X were stronger in umbilical artery than in the neonatal aorta, but Bcl-2 was weak in both arteries in immunohistochemistry. In the immunoblot analysis of UCs, the expression of the proapoptotic short isoform of Bcl-X was stronger than in other tissue, and caspase-3 was selectively activated, whereas it was not in the other components of the cardiovascular system. In contrast, the expression patterns of the FasAg and Fas ligand were similar in umbilical artery and aorta. Regulation of Bcl-2 family proteins was also observed in other vascular sites at which SMCs undergo apoptosis on hemodynamic changes during birth, such as the DA and the branching points of the great arteries from the aortic arch. Apoptosis is involved in the regression of human umbilical vessels and the DA and in the remodeling of the branching great arteries during the neonatal period, when Bcl-2 family proteins are likely to play a key role. A poptosis is a form of programmed cell death that plays a vital role in the maintenance of cell homeostasis in mature organisms, in morphogenesis during development, and in the pathogenesis of various disorders. 1 During perinatal morphogenesis of the cardiovascular system, apoptosis is known to be involved in the molding and shaping of the conduction system, including the atrioventricular node and His bundle, 2 and the remodeling of the vasculature according to perinatal hemodynamic changes such as the regression of the abdominal aorta. 3 The 2 most important changes in the circulation system at birth are the closure of umbilical vessels and the ductus arteriosus. In previous studies of ours and others, it has been demonstrated that certain unique features of umbilical vessels and the ductus arteriosus may contribute to closure after birth. First, they are both arterial systems that close at birth. Second, they contract when exposed to oxygen. 4,5 Third, they constrict sensitively to endothelin-1. 6,7 Fourth, they are composed of smooth muscle cells with adult phenotype, even during the neonatal period. 8 In addition to these physiological properties and phenotypical characteristics, other mechanisms, such as apoptosis, could be involved in the closure of these vessels, a process that is the most dramatic example of vascular remodeling at birth. It has recently been reported that apoptosis of smooth muscle cells was found in areas of cy...

Apoptosis During Cardiovascular Development

“…Coincident upregulation of proapoptotic members of the Bcl2 family (Bax and the short form of BclX) was observed in umbilical arteries. 84 Importantly, Kim et al 84 also observed apoptosis near large arterial branch sites postpartum, a finding consistent with a role for cell death in remodeling of arterial bifurcations during perinatal development.…”

“…Not surprisingly, extensive postnatal apoptosis occurs in vessels that regress after birth, ie, the umbilical arteries 66,84 and ductus arteriosus. 84 The extent to which death of these highly specialized cells is linked to hemodynamics is unknown.…”

“…84 The extent to which death of these highly specialized cells is linked to hemodynamics is unknown. Coincident upregulation of proapoptotic members of the Bcl2 family (Bax and the short form of BclX) was observed in umbilical arteries.…”

Oxygen increases ductus arteriosus smooth muscle cytosolic calcium via release of calcium from inositol triphosphate-sensitive stores

“…An acute increase in oxygen tension causes perinatal pulmonary vasodilation (3,26), even while it results in constriction of the DA (1,5). Initial closure of the DA in response to an increase in PO 2 is caused by vessel constriction (14), whereas long-term closure is accomplished through cell migration, apoptosis (25), and cell proliferation (4,15,18).…”

Soluble Fas Antigen and Soluble Fas Ligand in Intrauterine Growth Restriction

“…Accordingly, apoptosis seems to be vital during the transition from intra-to extrauterine life, since the former constitutes an immune privilege for the fetus [33] indicated by the special immunologic characteristics of umbilical cord blood cells [34] . In this respect, apoptosis is reportedly diminished in umbilical cord blood neutrophils compared to adult cells [34] .…”