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A Perturb-seq screen guided by species divergence uncovers pathways for collateral artery formation

Xiaochen Fan1,2, Ronghao Zhou3,4, Brian C Raftrey1

  • 1Department of Biology, Stanford University, Stanford, CA, USA.

Biorxiv : the Preprint Server for Biology
|May 18, 2026
PubMed

Insights

Guinea pigs have dense collateral arteries due to reduced activity of artery inhibitor and hypoxia pathways. Inhibiting these pathways in mice promotes collateral artery formation, offering new therapeutic targets.

Area of Science:

  • Cardiovascular Biology
  • Developmental Biology
  • Comparative Genomics

Background:

  • Collateral arteries are vital for rerouting blood flow around blockages, mitigating tissue damage in conditions like stroke and coronary artery disease.
  • Current therapeutic strategies to enhance collateral artery growth are limited by an incomplete understanding of their development.
  • Guinea pigs exhibit remarkable collateral artery density, conferring resistance to ischemic injury in the brain and heart.

Purpose of the Study:

  • To identify endothelial cell (EC) gene expression patterns linked to extensive collateral artery development by comparing guinea pig and mouse tissues using single-cell RNA sequencing (scRNA-seq).
  • To investigate the functional role of differentially expressed genes in artery EC specification using an in vivo Perturb-seq platform in mice.
  • To discover novel molecular targets for stimulating collateral artery formation.

Main Methods:

  • Comparative single-cell RNA sequencing (scRNA-seq) of guinea pig and mouse tissues.
  • Development of an in vivo Perturb-seq platform for functional genetic screening in mice.
  • Analysis of gene expression patterns in specific endothelial cell subsets (Esm1+ and Apln+).

Main Results:

  • Identified specific artery repressor genes that are downregulated in guinea pigs compared to mice.
  • Inhibition of these artery repressors in mice led to increased pial collateral artery abundance.
  • Demonstrated that reduced activity of WNT and hypoxia response pathways in ECs promotes arterial identity and collateral formation.

Conclusions:

  • Guinea pigs possess extensive collateral arteries due to decreased activity in artery inhibitor and hypoxia response pathways.
  • The study provides a novel strategy for discovering genes underlying species-specific traits.
  • Identified novel therapeutic targets, including specific WNT and hypoxia response genes, for promoting collateral artery formation.

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