Abstract In the human lung, the vast majority of gas exchanging units form after birth, amplifying the importance of physiologic lung development in infants. Pulmonary endothelial cells (EC) orchestrate the rapid expansion of the pulmonary microvasculature to support alveolarization. Signaling via proangiogenic molecules drive the formation of the pulmonary capillary network which is likely balanced by anti-angiogenic molecules. Endostatin, an anti-angiogenic fragment encoded by Col18a1 and derived from type XVIII collagen’s alpha chain, is secreted by vascular smooth muscle cells (VSMC), venous and lymphatic EC, and may play a role in both physiologic and pathophysiologic pulmonary angiogenesis. Endostatin is increased in infants at higher risk for bronchopulmonary dysplasia (BPD), alveolar capillary dysplasia (ACD), and trisomy 21, disease states characterized by compromised lung angiogenesis and alveolarization. Thus, we hypothesized that endostatin modulates angiogenesis and alveolarization during physiologic and pathologic lung development and treatment with endostatin antibody preserves or rescues lung angiogenesis and alveolarization in neonatal lung injury. We tested these hypotheses using multiple orthogonal approaches and found that: (i) Col18a1 expression is 8-fold increased in VSMC from hyperoxic, compared to normoxic mice at P7 and P21; (ii) whole-lung endostatin expression peaks at postnatal day (P) 21, corresponding with the slowing of lung angiogenesis; (iii) VSMC from neonatal mice exposed to hyperoxia (0.8 FiO2) from birth through P14 secrete dramatically more endostatin than normoxic counterparts; (iv) endostatin protein blocks and endostatin antibody (Ab) increases, in vitro angiogenesis;; (v) treatment with soluble endostatin Ab preserves or restores vascular density, radial alveolar counts, and alveolar size in hyperoxia- (FiO2=0.8 x ≤ 14d, recovery in normoxia) exposed neonatal mice at P7, P10, and P28; and (vi) bulk RNA-seq data suggesting that endostatin Ab protects pulmonary, especially general capillary, EC from hyperoxia-induced neonatal lung injury. These findings support the novel paradigm that endostatin derived from the pulmonary vasculature signals to EC to modulate angiogenesis and alveolarization and can be targeted to prevent or treat neonatal lung injury. We speculate that endostatin Ab may be a highly effective strategy to preserve lung development in infants at risk to develop BPD. This abstract is funded by: Karam Family Foundation
Cornfield et al. (Fri,) studied this question.