Genetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice

Xue Xiao, Lin Xu, Junhui Zhang, Xiaoyue Hu, Evanthia Pashos, George Tellides, Philip W. Shaul, Warren L. Lee, Carlos Fernandez-Hernando, Anne Eichmann, William C. Sessa, Sungwoon Lee, Hubertus Schleer, Hyojin Park, Erika Jang, Michael Boyer, Bo Tao, Ana María Gámez Méndez, Abhishek Singh, Ewa Folta-StogniewXinbo Zhang, Lingfeng Qin

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Low-density lipoprotein (LDL) accumulation in the arterial wall contributes to atherosclerosis initiation and progression 1 . Activin A receptor-like type 1 (ACVRL1, called activin-like kinase receptor (ALK1)) is a recently identified receptor that mediates LDL entry and transcytosis in endothelial cells (ECs) 2,3 . However, the role of this pathway in vivo is not yet known. In the present study, we show that genetic deletion of ALK1 in arterial ECs of mice substantially limits LDL accumulation, macrophage infiltration and atherosclerosis without affecting cholesterol or triglyceride levels. Moreover, a selective monoclonal antibody binding ALK1 efficiently blocked LDL transcytosis, but not bone morphogenetic protein-9 (BMP9) signaling, dramatically reducing plaque formation in LDL receptor knockout mice fed a high-fat diet. Thus, our results demonstrate that blocking LDL transcytosis into the endothelium may be a promising therapeutic strategy that targets the initiating event of atherosclerotic cardiovascular disease.
Original languageEnglish
Pages (from-to)438-448
Number of pages11
JournalNature cardiovascular research
Volume2
Issue number5
DOIs
Publication statusPublished - May 2023
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the NIH (grant no. R35HL139945) and an American Heart Association MERIT Award (to W.C.S.), an American Heart Association Postdoctoral Fellowship Award (to S.L.), a Canada Research Chair and an operating grant from the Canadian Institutes of Health Research (grant no. PJT168947 to W.L.L.). RVP measurements were made by the Internal Medicine Cardiology Center at Yale School of Medicine and blood pressure telemetry studies were conducted at The George M. O’Brien Kidney Center at Yale School of Medicine.

Funding Information:
This work was supported by the NIH (grant no. R35HL139945) and an American Heart Association MERIT Award (to W.C.S.), an American Heart Association Postdoctoral Fellowship Award (to S.L.), a Canada Research Chair and an operating grant from the Canadian Institutes of Health Research (grant no. PJT168947 to W.L.L.). RVP measurements were made by the Internal Medicine Cardiology Center at Yale School of Medicine and blood pressure telemetry studies were conducted at The George M. O’Brien Kidney Center at Yale School of Medicine.

Publisher Copyright:
© 2023, The Author(s).

Fingerprint

Dive into the research topics of 'Genetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice'. Together they form a unique fingerprint.

Cite this