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Background: Vascular occlusion and complex plexiform lesions are hallmarks of the pathology of severe pulmonary arterial hypertension (PAH) in patients. However, the mechanisms of obliterative vascular remodeling remain elusive; hence, current therapies have not targeted the fundamental disease-modifying mechanisms and result in only modest improvement in morbidity and mortality., Methods and Results: Mice with Tie2Cre-mediated disruption of Egln1 (encoding prolyl-4 hydroxylase 2 [PHD2]; Egln1(Tie2)) in endothelial cells and hematopoietic cells exhibited spontaneous severe PAH with extensive pulmonary vascular remodeling, including vascular occlusion and plexiform-like lesions, resembling the hallmarks of the pathology of clinical PAH. As seen in patients with idiopathic PAH, Egln1(Tie2) mice exhibited unprecedented right ventricular hypertrophy and failure and progressive mortality. Consistently, PHD2 expression was diminished in lung endothelial cells of obliterated pulmonary vessels in patients with idiopathic PAH. Genetic deletions of both Egln1 and Hif1a or Egln1 and Hif2a identified hypoxia-inducible factor-2α as the critical mediator of the severe PAH seen in Egln1(Tie2) mice. We also observed altered expression of many pulmonary hypertension-causing genes in Egln1(Tie2) lungs, which was normalized in Egln1(Tie2)/Hif2a(Tie2) lungs. PHD2-deficient endothelial cells promoted smooth muscle cell proliferation in part through hypoxia-inducible factor-2α-activated CXCL12 expression. Genetic deletion of Cxcl12 attenuated PAH in Egln1(Tie2) mice., Conclusions: These studies defined an unexpected role of PHD2 deficiency in the mechanisms of severe PAH and identified the first genetically modified mouse model with obliterative vascular remodeling and pathophysiology recapitulating clinical PAH. Thus, targeting PHD2/hypoxia-inducible factor-2α signaling is a promising strategy to reverse vascular remodeling for treatment of severe PAH., (© 2016 American Heart Association, Inc.)

Background: The integrity of endothelial monolayer is a sine qua non for vascular homeostasis and maintenance of tissue-fluid balance. However, little is known about the signaling pathways regulating regeneration of the endothelial barrier after inflammatory vascular injury., Methods and Results: Using genetic and pharmacological approaches, we demonstrated that endothelial regeneration selectively requires activation of p110γPI3K signaling, which thereby mediates the expression of the endothelial reparative transcription factor Forkhead box M1 (FoxM1). We observed that FoxM1 induction in the pulmonary vasculature was inhibited in mice treated with a p110γ-selective inhibitor and in Pik3cg(-/-) mice after lipopolysaccharide challenge. Pik3cg(-/-) mice exhibited persistent lung inflammation induced by sepsis and sustained increase in vascular permeability. Restoration of expression of either p110γ or FoxM1 in pulmonary endothelial cells of Pik3cg(-/-) mice restored endothelial regeneration and normalized the defective vascular repair program. We also observed diminished expression of p110γ in pulmonary vascular endothelial cells of patients with acute respiratory distress syndrome, suggesting that impaired p110γ-FoxM1 vascular repair signaling pathway is a critical factor in persistent leaky lung microvessels and edema formation in the disease., Conclusions: We identify p110γ as the critical mediator of endothelial regeneration and vascular repair after sepsis-induced inflammatory injury. Thus, activation of p110γ-FoxM1 endothelial regeneration may represent a novel strategy for the treatment of inflammatory vascular diseases., (© 2016 American Heart Association, Inc.)

Purpose: Recent results showed that plasminogen kringle 5 (K5) has improved inhibitory effect on human umbilical vein endothelial cells (HUVECs) viability when 5 acidic amino acids in NH2 terminal outside kringle domain were replaced by 5 serine residues (mutant K5, mK5). This study was designed to identify the enhanced antiangiogenic activity of mK5 in corneal neovascularization (CNV)., Methods: Alkali burn-induced CNV was induced and treated with K5 and mK5 for 11 days. CNV and inflammation were evaluated by the CNV area and the inflammatory index, respectively. At the end of treatment, the corneas were removed for terminal deoxynucleotidyl transferase dUTP nick end labeling detection and immunohistochemistry. The effects of mK5 and K5 on HUVECs apoptosis were tested by MTT, BrdU, and flow cytometry. The expression levels of pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) were detected by Western blot., Results: In a rat model of CNV induced by alkali, topical treatment with mK5 significantly decreased the neovascular area and inflammation compared with the wild-type K5-treated group. Meanwhile, mK5 and K5 specifically inhibited the HUVECs proliferation and induced vascular endothelial cell apoptosis in vitro and in vivo, and mK5 exerted higher apoptosis induction. Toward the mechanism of action, both mK5 and K5 significantly upregulated the expression of PEDF and mildly downregulated the expression of VEGF. The elevation of PEDF/VEGF ratio induced by mK5 was higher than that by K5., Conclusions: These findings suggest that mK5 has more effective therapeutic potential in CNV than wild-type K5.