# Targeting the Pial Collateral Circulation for Mitigation of Cerebral Ischemia

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $462,314

## Abstract

ABSTRACT
The major determinants of stroke severity after large-vessel occlusion are the location and duration of
occlusion and the amount of collateral blood flow. Unfortunately, pial collateral flow varies widely in patients
following acute ischemic stroke (AIS), correlating inversely with infarct volume and risk of hemorrhagic trans-
formation and directly with efficacy of thrombolysis and thrombectomy. Prior to our studies, clues to the cause
of this wide variation were largely unknown. In fact, much less is known about the vascular biology of
collaterals, compared to vessels of the general arterio-venous circulation. We recently identified that
collaterals form late in gestation in mice by a unique angiogenic process and signaling pathway, which we
termed “collaterogenesis”. And that collaterogenesis varies widely due to differences in genetic background,
resulting, as in humans, in large differences in collateral extent and stroke severity in the adult. Using genetic
mapping, we identified four loci that link to variation in collateral extent, and determined that the causal gene
and its causal SNPs at the largest locus is the novel gene, Rabep2. In preliminary analyses of stroke genetics
datasets, we have found that polymorphisms in human RABEP2 link to the incidence of acute ischemic stroke
and infarct size in AIS patients. To fully power these retrospective studies and also prospective studies that
are in the enrollment phase, we need to identify the causal genes for the three additional collateral QTL, as
well as other large-effect loci likely extant in the mouse species. We have also obtained preliminary results
answering a long-standing question—can additional collaterals be induced to form in adults. Preliminary results
show that systemic hypoxia and MCA occlusion both do so. And that both require Rabep2, recapitulating its
critical role in collaterogenesis in the embryo. The following Aims continue our overall goal to provide a deeper
understanding of the biology of these unique and important collateral vessels, and to translate the findings to
humans and their clinical care. Aim I will identify the candidate genes underlying the previously identified QTL,
Canq2, Canq3 and Canq4, and additional large-effect QTL, using the recently developed Diversity Outbred
and Collaborative Cross reference populations. Methods include high-resolution angiography and genetic
mapping, expression and in silico analyses. Aim II will use gene targeting to ascertain the causal genes at the
QTL identified in Aim I. Methods to assess outcome include determination of CBF, infarct volume, recovery of
neurological function and ischemic angiogenesis. Aim III will determine mechanisms of de novo formation of
new collaterals (NCF) induced by hypoxia following sustained decrease in inspired O2 and by MCA occlusion.
These studies will also aid identifying the key genes that drive collaterogenesis that harbor variants that
underlie the wide variation in collateral a...

## Key facts

- **NIH application ID:** 10376751
- **Project number:** 5R01NS083633-09
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Hua Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $462,314
- **Award type:** 5
- **Project period:** 2013-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376751

## Citation

> US National Institutes of Health, RePORTER application 10376751, Targeting the Pial Collateral Circulation for Mitigation of Cerebral Ischemia (5R01NS083633-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10376751. Licensed CC0.

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