HYPOXIA INCREASES BROMODEOXYURIDINE LABELING INDEXES IN BOVINE NEONATAL PULMONARY-ARTERIES

Thickening of peripheral pulmonary arteries (PA) in the pulmonary hype rtensive neonate has been well described morphologically, but less is known regarding the role of cell proliferation in either the normal or hypertensive neonatal PA. Thus we studied DNA synthetic indices in th e tunica media and tunica adventitia of four different sizes/generatio ns of PA in normoxic calves (n = 15) and calves exposed to hypobaric h ypoxia (n = 15) during the first 14 days of life. DNA synthetic indice s were determined by incorporation of the thymidine analogue bromodeox yuridine (BrdU). Hemodynamic studies confirmed a steady decline in PA pressure in normal neonatal calves during the first 2 wk of life and p rogressive pulmonary hypertension in the hypoxic group. Lungs were per fusion-fixed and pulmonary arteries were evaluated for BrdU incorporat ion by immunohistochemistry. DNA synthetic indices (BrdU-labeled cells /1,000 cells) in the tunica media from normoxic calves were highest be tween 4 and 7 days postpartum and decreased to their lowest levels by day 14. The highest indices were observed in smaller generations of PA in the normoxic newborn. Adventitial cells exhibited the same general pattern of BrdU incorporation except that the post-partum peak occurr ed earlier, at 1 to 4 days. Exposure to hypoxia significantly increase d (P = 0.001) DNA synthetic indices in both the tunica media and adven titia. The highest DNA synthetic indices were observed in smaller-gene ration vessels. These findings indicate that the fraction of cells tra versing the S phase (i.e., actively replicating in the cell cycle) in the normal neonatal pulmonary vasculature during transition are initia lly high compared to reported rates in hilar PA from adult rats, but t hen decrease by 14 days after birth. Further, exposure to hypoxia duri ng transition dramatically increases and prolongs pulmonary vascular c ell proliferation. We conclude that structural remodeling in the hyper tensive neonatal PA is due partly to increased cell proliferation in t he tunica media and adventitia.