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Treatment with Atorvastatin During Vascular Remodeling Promotes Pericyte-Mediated Blood-Brain Barrier Maturation Following Ischemic Stroke

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Abstract

We previously showed that newly formed vessels in ischemic rat brain have high blood-brain barrier (BBB) permeability at 3 weeks after stroke due to a lack of major endothelial tight junction proteins (TJPs), which may exacerbate edema in stroke patients. Atorvastatin was suggested a dose-dependent pro-angiogenic effect and ameliorating BBB permeability beyond its cholesterol-lowering effects. This study examined our hypothesis that, during vascular remodeling after stroke, treatment with atorvastatin could facilitate BBB maturation in remodeling vasculature in ischemic brain. Adult spontaneously hypertensive rats underwent middle cerebral artery occlusion with reperfusion (MCAO/RP). Atorvastatin, at dose of 3 mg/kg, was delivered daily starting at 14 days after MCAO/RP onset for 7 days. The rats were studied at multiple time points up to 8 weeks with multimodal-MRI, behavior tests, immunohistochemistry, and biochemistry. The delayed treatment of atorvastatin significantly reduced infarct size and BBB permeability, restored cerebral blood flow, and improved the neurological outcome at 8 weeks after MCAO/RP. Postmortem studies showed that atorvastatin promoted angiogenesis and stabilized the newly formed vessels in peri-infarct areas. Importantly, atorvastatin facilitated maturation of BBB properties in the new vessels by promoting endothelial tight junction (TJ) formation. Further in vivo and in vitro studies demonstrated that proliferating peri-vascular pericytes expressing neural-glial antigen 2 (NG2) mediated the role of atorvastatin on BBB maturation through regulating endothelial TJ strand formations. Our results suggested a therapeutic potential of atorvastatin in facilitating a full BBB integrity and functional stroke recovery, and an essential role for pericyte-mediated endothelial TJ formation in remodeling vasculature.

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Acknowledgments

We thank Ms. Kelsey Duval for English editing. Confocal images in this paper were generated in the University of New Mexico Cancer Center Fluorescence Microscopy Facility. Electron microscopy images in this paper were generated in the University of New Mexico Department of Cell Biology and Physiology Electron Microscopy Facility.

Funding

This study was supported by grants from the American Heart Association (13GRNT17060032) and National Institutes of Health (1RF1NS110724) to Dr. Yi Yang.

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Authors and Affiliations

  1. College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA

    Yirong Yang

  2. Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131-0001, USA

    Lisa Y. Yang, Victor M. Salayandia, Michel Torbey & Yi Yang

  3. Center for Memory and Aging, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA

    Jeffrey F. Thompson

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  1. Yirong Yang
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Yang, Y., Yang, L.Y., Salayandia, V.M. et al. Treatment with Atorvastatin During Vascular Remodeling Promotes Pericyte-Mediated Blood-Brain Barrier Maturation Following Ischemic Stroke. Transl. Stroke Res. 12, 905–922 (2021). https://doi.org/10.1007/s12975-020-00883-0

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