Ligating the Ductus Arteriosus before birth Remodels the Pulmonary Vasculature of the Lamb

Abstract

ABSTRACT. The clinical syndrome of persistent pulmonary hypertension of the newborn includes a developmentally abnormal pulmonary microvasculature which contains excessive amounts of muscle and which cannot adapt to air breathing in the perinatal period. Surgical ligation of the ductus arteriosus of the fetal lamb has produced a physiologic model of pulmonary hypertension of the newborn. The aim of the present investigation is to determine whether surgical ligation of the ductus arteriosus in fetal sheep produces anatomic changes in the pulmonary blood vessels. The pulmonary vasculature of seven neonatal lambs that underwent surgical ligation of the ductus arteriosus from 6 to 17 d before birth was compared to that of five control lambs with a patent ductus arteriosus without fetal surgery and three control lambs with a patent ductus arteriosus that underwent sham surgery. Quantitative microscopic analysis of the barium gelatin-filled peripheral pulmonary vascular bed revealed an increase in thc proportion of partially and fully muscularized pulmonary arteries a t the level of the terminal bronchiole and within the acinus (p < 0.0001). This finding demonstrates that medial muscle develops in areas of the distal pulmonary vascular bed where it is normally absent. Periadventitial fibrosis surrounding intraacinar pulmonary arteries was also present. No change in the number of small intraacinar arteries was detected. This structural remodeling of the peripheral pulmonary vascular bed was initiated in utero by ductus arteriosus occlusion. Prenatal closure of the ductus arteriosus for 6 to 17 d in fetal lambs produces anatomic changes in small pulmonary arteries of the newborn lamb. These anatomic changes are similar to pathologic alterations reported in human neonates dying with idiopathic persistent pulmonary hypertension of the newborn. The clinical syndrome of idiopathic PPHN is characterized morphologically by the abnormal presence of muscle in the walls of the smallest pulmonary artery branches (1). The etiology of PPHN occurring in the absence of primary cardiac, pulmonary,

Prenatal Features of Ductus Arteriosus Constriction and Restrictive Foramen Ovale in d-Transposition of the Great Arteries

“…Observations in human and animal fetuses with normal cardiovascular anatomy have shown that prenatal constriction of the ductus arteriosus produces anatomic changes in small pulmonary arteries, 22,23 similar to neonates with idiopathic persistent pulmonary hypertension. 24 This may be related to an increase in pulmonary blood flow and pressure.…”

Increased p22phox/Nox4 Expression Is Involved in Remodeling Through Hydrogen Peroxide Signaling in Experimental Persistent Pulmonary Hypertension of the Newborn

“…These newborn lambs display increased PA pressure, pulmonary vascular remodeling, and other physiological changes consistent with clinical PPHN (31,49). Recent evidence suggests that PPHN lambs also exhibit elevated pulmonary vascular oxidant stress and a diminished antioxidant activity relative to control lambs (7,47), which may promote vasoconstriction directly and by impairing the activity of endothelial nitric oxide synthase (eNOS) and downstream cyclic guanozine monophosphate (cGMP) signaling (5,14,37).…”

Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells

“…Intrauterine hypoxemia, infection, hyperglycemia, and drug exposure can result in an incomplete response to perinatal vasodilator stimuli and persistently elevated pulmonary arterial blood pressure, limited pulmonary blood flow, and severe central hypoxemia. Persistent pulmonary hypertension of the newborn (PPHN) is characterized by extrapulmonary shunting of blood across the patent foreman ovale and through the patent ductus arteriosus (DA), severe hypoxemia, high levels of circulating endothelin-1, decreased nitric oxide production, and vascular remodeling due to increased cell proliferation (1,3,13,14,29).…”

“…Intrauterine hypoxemia, infection, hyperglycemia, and drug exposure can result in an incomplete response to perinatal vasodilator stimuli and persistently elevated pulmonary arterial blood pressure, limited pulmonary blood flow, and severe central hypoxemia. Persistent pulmonary hypertension of the newborn (PPHN) is characterized by extrapulmonary shunting of blood across the patent foreman ovale and through the patent ductus arteriosus (DA), severe hypoxemia, high levels of circulating endothelin-1, decreased nitric oxide production, and vascular remodeling due to increased cell proliferation (1,3,13,14,29).Previous work from our laboratory demonstrated that pulmonary artery smooth muscle cells (PA SMC) derived from late-gestation fetal lambs directly sense an acute increase in oxygen tension and respond with activation of a calciumsensitive K ϩ (K Ca ) channel, membrane hyperpolarization, and a decrease in intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (23). In contrast, in PA SMC derived from an ovine model of PPHN, K Ca channel expression is diminished, and an acute increase in oxygen tension has no effect on [Ca 2ϩ ] i (18).…”