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Flow-mediated endothelial remodeling and inflammation drive developmental vascular susceptibility in ldlr loss of

Aryan Kaveh1,2, Antonio G Salazar-Martin3,4, Wei Dai5

  • 1Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. aryan.kaveh@helsinki.fi.

Nature Communications
|May 21, 2026
PubMed

Insights

Low-density lipoprotein receptor loss causes early atherosclerosis by stressing endothelial cells and promoting inflammation. Heat shock protein 70 (hsp70) upregulation disrupts blood vessel remodeling and healing in zebrafish models.

Area of Science:

  • Cardiovascular Biology
  • Developmental Biology
  • Zebrafish Models

Background:

  • Atherosclerosis, a major cardiovascular disease, involves lipid metabolism, endothelial dysfunction, and inflammation.
  • Early mechanisms of atherosclerosis are not fully understood.
  • Low-density lipoprotein receptor (LDLR) loss-of-function is a common monogenic cause.

Purpose of the Study:

  • Investigate the developmental origins of atherosclerosis using LDLR knockout (ldlr-/-) zebrafish.
  • Identify early cellular and molecular changes contributing to atherosclerosis development.

Main Methods:

  • Utilized single-cell RNA-sequencing in embryonic ldlr-/- zebrafish under varying flow conditions.
  • Conducted genetic and pharmacological studies to assess heat shock protein 70 (hsp70) function.
  • Analyzed vascular remodeling, apoptosis, ciliogenesis, myelopoiesis, thrombogenicity, and neutrophil recruitment.

Main Results:

  • Identified stressed endothelial cells overexpressing hsp70 in embryonic ldlr-/- zebrafish.
  • Demonstrated flow-dependent hsp70 induction in zebrafish and human endothelial cells.
  • Showed hsp70 upregulation inhibits vascular apoptosis and ciliogenesis, disrupting angiogenic remodeling.
  • Observed amplified inflammation, impaired regenerative angiogenesis, and heightened neutrophil recruitment in ldlr-/- zebrafish.

Conclusions:

  • Aberrant flow-mediated endothelial remodeling and inflammation converge during embryogenesis in LDLR deficiency.
  • These processes drive vascular susceptibility to hemodynamic and other stressors.
  • Findings provide insights into the developmental basis of atherosclerosis.

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