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 abundance in the adult. They are also required to power studies currently underway to test the orthologous genes in humans. In addition, they will open up a new area of basic research, NCF induced by ischemia, which may lead to novel therapies to treat obstructive disease.

Public Health Relevance

A major determinant of the severity of stroke is the abundance in the brain of a highly specialized type of blood vessel, called collaterals, which provide an alternative route of blood flow when an artery suddenly becomes blocked. Unfortunately, the number and diameter of these vessels various dramatically among both mice and humans due primarily to differences in genetic background, but the responsible genes are unknown. A major goal of this study is to identify the key genes causing this variation in mice, so that their potential importance in humans can be tested and novel therapies to treat obstructive disease investigated in the future.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Koenig, James I
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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