Youyang Zhao

Recovery of endothelial barrier integrity after vascular injury is vital for endothelial homeostasis and resolution of inflammation. Endothelial dysfunction plays a critical role in the initiation and progression of vascular diseases such as acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and atherosclerosis. A part of the research in the lab, employing genetically modified mouse models of human diseases, endothelial progentior cells/stem cells, and translational research approach as well as nanomedicine, is to elucidate the molecular mechanisms of endothelial regeneration and resolution of inflammatory injury and determine how aging and epigenetics regulate these processes (J Clin Invest 2006, 116:2333; J Exp Med 2010, 207:1675; Circulation 2016, 133:2447). We are also studying the role of endothelial cells in regulating macrophage functional polarization and resolving inflammatory lung injury. These studies will identify druggable targets leading to novel therapeutic strategies to activate the intrinsic endothelial regeneration program to restore endothelial barrier integrity and reverse edema formation for the prevention and treatment of ARDs in patients.

Pulmonary hypertension is a progressive disease with poor prognosis and high mortality. We are currently investigating the molecular basis underlying the pathogenesis. We have recently identified the first mouse model of PAH with obliterative vascular remodeling including vascular occlusion and formation of plexiform-like lesions resembling the pathology of clinical PAH (Circulation 2016, 133:2447). Our previous studies also show the critical role of oxidative/nitrative stress in the pathogenesis of PAH as seen in patients (PNAS 2002, 99:11375; J Clin Invest 2009, 119:2009), With these unique models and lung tissue and cells from IPAH patients, we will define the molecular and cellular mechanisms underlying severe vascular remodeling and provide novel therapeutic approaches for this devastating disease.

Dai Z, Li M, Wharton J, Zhu MM, Zhao YY. PHD2 deficiency in endothelial cells and hematopoietic cells induces obliterative vascular remodeling and severe pulmonary arterial hypertension in mice and humans through HIF-2alpha.Circulation. 133:2447-2458, 2016.

Huang X, Dai Z, Cai L, Sun K, Cho J, Albertine KH, Malik AB, Schraufnagel DE, Zhao YY. Endothelial p110gammaPI3K mediates endothelial regeneration and vascular repair following inflammatory vascular injury. Circulation. 133:1093-1103, 2016.

Tran K, Zhang X, Predescu D, Huang X, Machado RF, Gothert JR, Malik AB, Valyi-Nagy T, Zhao YY. Endothelial Beta-catenin signaling is required for maintaining adult blood-brain barreri integrity and central nervous system homeostasis.Circulation. 133:177-186, 2016.

Zhao YD, Huang XJ, Yi F, Dai Z, Qian Z, Tiruppathi C, Tran K, Zhao YY. Endothelial FoxM1 mediates bone marrow progenitor cell-induced vascular repair and resolution of inflammation following inflammatory lung injury. Stem Cells.32:1855-1864, 2014.

Mirza MK, Sun Y, Zhao YD, SK Potula HH, Frey RS, Vogel SM, Malik AB, Zhao YY. FoxM1 regulates re-annealing of endothelial adherens junctions through transcriptional control of b-catenin. J Exp Med. 207:1675-1685, 2010.

Zhao YY*, Zhao YD, Mirza MK, Huang JH, SK Potula HH, Vogel SM, Brovkovych V, Yuan JXJ, Wharton J, Malik AB. Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through protein kinase G nitration. J Clin Invest.119:2009-2018, 2009. (*Correspondent).

Zhao YY*, Gao XP, Zhao YD, Mirza MK, Frey RS, Kalinichenko VV, Wang IC, Costa RH, Malik AB. Endothelial cell-restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury. J Clin Invest. 116:2333-2343, 2006. (*, Correspondent).

Zhao YY, Liu Y, Stan RV, Fan L, Gu Y, Dalton N, Chu PH, Peterson K, Ross J Jr, Chien KR. Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc Natl Acad Sci USA. 99:11375-11380, 2002.

Crone S*, Zhao YY*, Fan L, Gu YS, Minamisawa S, Peterson K, Chen J, Kahn R, Condorelli G, Ross J Jr, Chien KR, and Lee KF. ErbB2 myocyte survival pathways are essential in the preventio of dilated cardiomyopathy. Nat Med. 8:459-465. (*, contributed equally).