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A High Output Method to Isolate Cerebral Pericytes from Mouse
Published on: January 14, 2020
Pathological pericyte expansion and impaired endothelial cell-pericyte communication in endothelial Rbpj deficient
Samantha Selhorst1,2, Sera Nakisli1,3, Shruthi Kandalai1,2
1Department of Biological Sciences, Ohio University, Athens, OH, United States.
Insights
Pericytes expand and change their molecular profile in a mouse model of Recombination signal binding protein for immunoglobulin kappa J region (Rbpj)-mediated brain arteriovenous malformation (AVM). These changes impact cell communication, suggesting pericytes as therapeutic targets for AVM.
Area of Science:
- Neuroscience
- Vascular Biology
- Cell Biology
Background:
- Pericytes are crucial for vascular development and homeostasis, particularly in the brain.
- Their role in neurovascular disease pathogenesis is not fully understood, with conflicting reports on coverage and infiltration.
- Brain arteriovenous malformations (AVMs) are complex vascular lesions where pericyte involvement requires further investigation.
Purpose of the Study:
- To investigate the effects on pericytes during the pathogenesis of Recombination signal binding protein for immunoglobulin kappa J region (Rbpj)-mediated brain arteriovenous malformation (AVM) in a mouse model.
- To test the hypothesis that pericyte expansion and Platelet-derived growth factor B/Platelet-derived growth factor receptor β (Pdgf-B/Pdgfrβ)-dependent endothelial cell-pericyte communication are affected in Rbpj-mediated brain AVM.
Main Methods:
- Utilized an endothelial loss-of-function mouse model with Rbpj deletion to induce brain AVM.
- Analyzed pericyte coverage, morphology, proliferation, and expression of key molecular markers (Pdgfrβ, N-cadherin, CD146) in mutant versus control brains.
- Assessed endothelial cell expression of N-cadherin.
Main Results:
- Endothelial deletion of Rbpj led to pathological expansion of pericyte coverage in brain and retinal vasculature.
- Pericyte expansion in Rbpj-mutant brains was primarily due to cytoplasmic process extension, not increased proliferation.
- Pericytes in Rbpj-mutant brains exhibited decreased expression of Pdgfrβ, N-cadherin, and CD146, impairing cell communication.
- Endothelial cells in mutant brains showed increased N-cadherin expression, potentially as a compensatory mechanism.
Conclusions:
- Endothelial Rbpj deletion induces significant cellular and molecular alterations in brain pericytes during AVM pathogenesis.
- Pericyte expansion and altered molecular profiles suggest a complex response to vascular abnormalities.
- Pericytes represent potential therapeutic targets for Rbpj/Notch-related brain AVMs.
Abstract:
Pericytes, like vascular smooth muscle cells, are perivascular cells closely associated with blood vessels throughout the body. Pericytes are necessary for vascular development and homeostasis, with particularly critical roles in the brain, where they are involved in regulating cerebral blood flow and establishing the blood-brain barrier. A role for pericytes during neurovascular disease pathogenesis is less clear-while some studies associate decreased pericyte coverage with select neurovascular diseases, others suggest increased pericyte infiltration in response to hypoxia or traumatic brain injury. Here, we used an endothelial loss-of-function Recombination signal binding protein for immunoglobulin kappa J region (Rbpj)/Notch mediated mouse model of brain arteriovenous malformation (AVM) to investigate effects on pericytes during neurovascular disease pathogenesis. We tested the hypothesis that pericyte expansion, via morphological changes, and Platelet-derived growth factor B/Platelet-derived growth factor receptor β (Pdgf-B/Pdgfrβ)-dependent endothelial cell-pericyte communication are affected, during the pathogenesis of Rbpj mediated brain AVM in mice. Our data show that pericyte coverage of vascular endothelium expanded pathologically, to maintain coverage of vascular abnormalities in brain and retina, following endothelial deletion of Rbpj. In Rbpj-mutant brain, pericyte expansion was likely attributed to cytoplasmic process extension and not to increased pericyte proliferation. Despite expanding overall area of vessel coverage, pericytes from Rbpj-mutant brains showed decreased expression of Pdgfrβ, Neural (N)-cadherin, and cluster of differentiation (CD)146, as compared to controls, which likely affected Pdgf-B/Pdgfrβ-dependent communication and appositional associations between endothelial cells and pericytes in Rbpj-mutant brain microvessels. By contrast, and perhaps by compensatory mechanism, endothelial cells showed increased expression of N-cadherin. Our data identify cellular and molecular effects on brain pericytes, following endothelial deletion of Rbpj, and suggest pericytes as potential therapeutic targets for Rbpj/Notch related brain AVM.
