LAUSR

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by disordered and dysfunctional angiogenesis leading to small vessel loss and an obliterative vasculopathy. The pathogenesis of PAH is not fully understood but multiple studies have demonstrated links between elevated angiostatic factors, disease severity, and adverse clinical outcomes. Endostatin (ES), one such circulating angiostatic peptide, is the cleavage product of the proteoglycan collagen 18a1 (Col18a1). Elevated serum ES is associated with increased mortality and disease severity in PAH. A non-synonymous variant of ES (aspartic acid to asparagine substitution at amino acid 104, D to N104), is associated with differences in PAH survival. While Col18a1/ES expression is markedly increased in remodeled pulmonary vessels in PAH, the impact of ES on pulmonary endothelial cell (PEC) biology and molecular contributions to PAH severity remain undetermined. Here, we characterize the effects of exogenous ES on human PEC biology and signaling. We demonstrate that ES inhibits PEC migration, proliferation and cell survival, with significant differences between human variants, indicating they are functional genetic variants. Endostatin promotes proteasome-mediated degradation of the transcriptional repressor ID1, increasing expression and release of thrombospondin-1 (TSP-1). ES inhibits PEC migration via an ID1-TSP-1-CD36 dependent pathway, in contrast to proliferation and apoptosis which requires both CD36 and CD47. Collectively, the data implicates ES as a novel negative regulator of ID1 and an upstream propagator of an angiostatic signal cascade converging on CD36 and CD47, providing insight into the cellular and molecular effects of a functional genetic variant linked to altered outcomes PAH.