DOI: 10.1161/str.55.suppl_1.tmp5 ISSN: 0039-2499

Abstract TMP5: Mutation of Pdgfrβ Enhances the Severity of Brain Arteriovenous Malformation on Endoglin Mutant Mice Through Exacerbation of Angiogenesis and Inflammation

Alka Yadav, Leandro Barbosa Do Prado, Chaoliang Tang, Sonali Shaligram, Rich Liang, Kelly Press, Jasneet Dhaliwal, Ethan A Winkler, Hua Su
  • Advanced and Specialized Nursing
  • Cardiology and Cardiovascular Medicine
  • Neurology (clinical)

Background and Purpose: Brain arteriovenous malformations (bAVMs) are tangles of abnormal vessels shunting blood directly from arteries to veins. Reduction of pericytes is correlated with bAVM hemorrhage. The PDGFB/PDGFRβ signaling plays important roles in regulating pericyte recruitment during angiogenesis.

Hypothesis: Mutation of PDGFRβ causes cerebrovascular malformation and enhances bAVM severity in endoglin ( Eng ) deficient mice.

Methods: Three mouse models were used: (1) Pdgfrβ F7 (F7) mice that have mutations disrupting most Pdgfrβ signaling, (2) Pdgfb icreER; Eng f/f mice that have Pdgfb promoter driving, tamoxifen (TM) inducible cre expression in endothelial cells (ECs) and a floxed Eng gene; and (3) PdgfbicreER; Eng f/f ;F7 +/- mice were used. Brain angiogenesis was induced by intra-parenchymal injection of AAV-VEGF. BAVMs were induced in PdgfbicreER; Eng f/f and PdgfbicreER; Eng f/f ;F7 +/- mice by inducting EC Eng deletion through TM treatment and brain angiogenesis through intra-brain injection of AAV-VEGF. BAVM phenotypes were analyzed 8-weeks after model induction by latex vascular cast to detect arteriovenous shunts, immunostaining to analyze vessel morphology, Prussian blue staining to quantify microhemorrhage and RNAseq to investigate gene expression profiles.

Results: Dysplastic vessels with reduced pericyte coverage were detected in the brain and brain angiogenic region of F7 +/- and F7 +/+ mice. AVM like vessels were detected in the brain of 16% F7 +/- and 66% of F7 +/+ mice. F7 mutation increases bAVM penetrance in Eng deficient mice (71% vs 50%), dysplastic vessels and microhemorrhage. RNAseq data revealed that mutation of Pdgfrb increased the expression of pro-angiogenic and endothelial cell proliferation genes and genes promote cell migration and inflammation in the bAVMs of Eng mutant mice.

Conclusion: Pdgfrβ mutation exacerbates the severity of bAVM in Eng mutant mice by enhancing angiogenesis and inflammation.

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