Hwangbo, Cheol Lee, Heon-Woo Kang, Hyeseon Ju, Hyekyung Wiley, David S. Papangeli, Irinna Han, Jinah Kim, Jun-Dae Dunworth, William P. Hu, Xiaoyue Lee, Seyoung El-Hely, Omar Sofer, Avraham Pak, Boryeong Peterson, Laura Comhair, Suzy Hwang, Eun Mi Park, Jae-Yong Thomas, Jean-Leon Bautch, Victoria L. Erzurum, Serpil C. Chun, Hyung J. Jin, Suk-Won 2024-01-20T01:30:20Z 2024-01-20T01:30:20Z 2021-09-05 2017-06-06 0009-7322 https://pubs.kist.re.kr/handle/201004/122640 BACKGROUND: Bone morphogenetic protein (BMP) signaling has multiple roles in the development and function of the blood vessels. In humans, mutations in BMP receptor type 2 (BMPR2), a key component of BMP signaling, have been identified in the majority of patients with familial pulmonary arterial hypertension (PAH). However, only a small subset of individuals with BMPR2 mutation develops PAH, suggesting that additional modifiers of BMPR2 function play an important role in the onset and progression of PAH. METHODS: We used a combination of studies in zebrafish embryos and genetically engineered mice lacking endothelial expression of Vegfr3 to determine the interaction between vascular endothelial growth factor receptor 3 (VEGFR3) and BMPR2. Additional in vitro studies were performed by using human endothelial cells, including primary lung endothelial cells from subjects with PAH. RESULTS: Attenuation of Vegfr3 in zebrafish embryos abrogated Bmp2b-induced ectopic angiogenesis. Endothelial cells with disrupted VEGFR3 expression failed to respond to exogenous BMP stimulation. Mechanistically, VEGFR3 is physically associated with BMPR2 and facilitates ligand-induced endocytosis of BMPR2 to promote phosphorylation of SMADs and transcription of ID genes. Conditional, endothelial-specific deletion of Vegfr3 in mice resulted in impaired BMP signaling responses, and significantly worsened hypoxia-induced pulmonary hypertension. Consistent with these data, we found significant decrease in VEGFR3 expression in pulmonary arterial endothelial cells from human PAH subjects, and reconstitution of VEGFR3 expression in PAH pulmonary arterial endothelial cells restored BMP signaling responses. CONCLUSIONS: Our findings identify VEGFR3 as a key regulator of endothelial BMPR2 signaling and a potential determinant of PAH penetrance in humans. English LIPPINCOTT WILLIAMS & WILKINS VEGF-C ANGIOGENESIS MUTATIONS CELLS ENDOCYTOSIS COMPONENTS DISTINCT PATHWAY BMPR2 Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension Article 10.1161/CIRCULATIONAHA.116.025390 1 CIRCULATION, v.135, no.23, pp.2288 - + CIRCULATION 135 23 2288 + scie scopus 000402636700015 2-s2.0-85018831067 Cardiac & Cardiovascular Systems Peripheral Vascular Disease Cardiovascular System & Cardiology Article VEGF-C ANGIOGENESIS MUTATIONS CELLS ENDOCYTOSIS COMPONENTS DISTINCT PATHWAY BMPR2 bone morphogenetic protein receptors, type II endothelial cells FLT4 protein, human hypertension, pulmonary