2. Academic Validation
  3. BMPR1A Promotes ID2-ZEB1 Interaction to Suppress Excessive Endothelial to Mesenchymal Transition

BMPR1A Promotes ID2-ZEB1 Interaction to Suppress Excessive Endothelial to Mesenchymal Transition

  • Cardiovasc Res. 2022 Sep 27;cvac159. doi: 10.1093/cvr/cvac159.
Heon Woo Lee 1,  Takaomi Adachi 2,  Boryeong Pak 3,  Saejeong Park 1,  Xiaoyue Hu 1,  Woosoung Choi 3,  Piotr S Kowalski 4,  C Hong Chang 1,  Katharine R Clapham 5,  Aram Lee 1 6,  Irinna Papangeli 1,  Jongmin Kim 6,  Orjin Han 3,  Jihwan Park 3,  Daniel G Anderson 4,  Michael Simons 1,  Suk Won Jin 1 3,  Hyung J Chun 1 7
Affiliations

Affiliations

  • 1 Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
  • 2 Meiji University of Integrative Medicine, Kyoto, Japan.
  • 3 School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.
  • 4 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 5 Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA 02127.
  • 6 Division of Biological Sciences, Sookmyung Women's University, Seoul 04310, Korea.
  • 7 VA Connecticut Healthcare System, 950 Campbell Ave, 111B, West Haven, CT 06516.
PMID: 36166408 DOI: 10.1093/cvr/cvac159
Abstract

Aims: Components of BMP signaling have been implicated in both pathogenesis of pulmonary arterial hypertension (PAH) and endothelial-mesenchymal transition (EndoMT). In particular, the importance of BMP Type 2 Receptor (BMPR2) in these processes have been extensively analyzed. However, the contribution of BMP Type1 Receptors (BMPR1s) to the onset of PAH and EndoMT remains poorly understood. BMPR1A, one of BMPR1s, was recently implicated in the pathogenesis of PAH, and was found to be downregulated in the lungs of PAH patients, neither the downstream mechanism nor its contribution to EndoMT has been described. Therefore, we aim to delineate the role of endothelial BMPR1A in modulating EndoMT and pathogenesis of PAH.

Methods and results: We find that BMPR1A knockdown in endothelial cells (ECs) induces hallmarks of EndoMT, and deletion of endothelial Bmpr1a in adult mice (Bmpr1aiECKO) leads to development of PAH-like symptoms due to excessive EndoMT. By lineage tracing, we show that endothelial-derived smooth muscle cells are increased in endothelial Bmpr1a deleted mice. Mechanistically, we identify ZEB1 as a primary target for BMPR1A in this setting; Upon BMPR1A activation, ID2 physically interacts and sequesters ZEB1 to attenuate transcription of Tgfbr2, which in turn lowers the responses of ECs toward TGF-β stimulation and prevents excessive EndoMT. In Bmpr1aiECKO mice, administering endothelial targeting lipid nanoparticles containing siRNA against Tgfbr2 effectively ameliorate PAH, reiterating the importance of BMPR1A-ID2/ZEB1-TGFBR2 axis in modulating progression of EndoMT and pathogenesis of PAH.

Conclusions: We demonstrate that BMPR1A is key to maintain endothelial identity and to prevent excessive EndoMT. We identify BMPR1A-induced interaction between ID2 and ZEB1 is the key regulatory step for onset of EndoMT and pathogenesis of PAH. Our findings indicate that BMPR1A-ID2/ZEB1-TGFBR2 signaling axis could serve as a potential novel therapeutic target for PAH and other EndoMT-related vascular disorders.

Keywords

BMP signaling; BMPR1A; EndoMT; pulmonary arterial hypertension; vascular remodeling.

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