한빛사논문
- 조회1,318
Cheol Hwangbo, PhD1*; Heon-Woo Lee, PhD1*; Hyeseon Kang, MS1*; Hyekyung Ju, MS1; David S. Wiley, PhD2; Irinna Papangeli, PhD1; Jinah Han, PhD1; Jun-Dae Kim, PhD1; William P. Dunworth, PhD1; Xiaoyue Hu, BA1; Seyoung Lee, PhD1; Omar El-Hely1; Avraham Sofer, MD1; Boryeong Pak, MS3; Laura Peterson, BA4; Suzy Comhair, PhD4; Eun Mi Hwang, PhD5; Jae-Yong Park, PhD5,6; Jean-Léon Thomas, PhD7,8; Victoria L. Bautch, PhD2; Serpil C. Erzurum, MD4; Hyung J. Chun, MD1; Suk-Won Jin, PhD1,3
1Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT; 2Department of Biology, University of North Carolina, Chapel Hill, NC; 3School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea; 4Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; 5Center for Functional Connectomics (CFC), Korea Institute of Science and Technology
(KIST), Seoul, Korea; 6School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Korea; 7Department of Neurology, Yale University School of Medicine, New Haven, CT; 8Université Pierre and Marie Curie–Paris 6, CRICM & INSERM, UMRS 975 & APHP, Groupe Hospitalier Pitié-Salpètrière, Paris, France
*These authors contributed equally
Address for Correspondence : Hyung J. Chun, MD and Suk-Won Jin, PhD
Abstract
Background - Bone Morphogenetic Protein (BMP) signaling has multiple roles in the development and function of the blood vessels. In humans, mutations in BMP type 2 receptors (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 utilized a combination of studies in zebrafish embryos and genetically engineered mice lacking endothelial expression of Vegfr3 to determine the interaction between VEGFR3 and BMPR2. Additional in vitro studies were performed using human endothelial cells, including primary endothelial cells from subjects with PAH.
Results - Attenuation of Vegfr3 in zebrafish embryos abrogated Bmp2b-induced ectopic angiogenesis. Endothelial cells (ECs) 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 (PH). Consistent with this data, we found significant decrease in VEGFR3 expression in pulmonary arterial endothelial cells (PAECs) from human PAH subjects, and reconstitution of VEGFR3 expression in PAH PAECs 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.
bone morphogenetic protein, vascular endothelial growth factor receptor, pulmonary hypertension, endothelial cell, signal transduction
논문정보
- Research article
- 2017년 04월 (BRIC 등록일 2017-05-02)
- 국내(교신)+국외 연구진
- 생명과학 > 유전학
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