Continued dysfunction of capillary pericytes promotes no-reflow after experimental stroke in vivo

Shrouder, J. J.; Filser, S.; Varga, D. P.; Mamrak, U.; Besson-Girard, S.; Bulut-Impraim, B.; Seker, F. B.; Gesierich, B.; Laredo, F.; Wehn, A. C.; Khalin, I.; Bayer, P.; Liesz, A.; Gokce, O.; Plesnila, N.

doi:10.1101/2023.03.06.531258

bioRxiv · 10.1101/2023.03.06.531258

Continued dysfunction of capillary pericytes promotes no-reflow after experimental stroke in vivo

Shrouder, J. J.·Filser, S.·Varga, D. P.·Mamrak, U.·Besson-Girard, S.·Bulut-Impraim, B.·Seker, F. B.·Gesierich, B.·Laredo, F.·Wehn, A. C.·Khalin, I.·Bayer, P.·Liesz, A.·Gokce, O.·Plesnila, N.

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Abstract

Incomplete reperfusion of the microvasculature ("no-reflow") after ischemic stroke damages salvageable brain tissue. Previous ex-vivo studies suggest pericytes are vulnerable to ischemia and may exacerbate no-reflow, but the viability of pericytes and their association with no-reflow remains underexplored in vivo. Using longitudinal in vivo 2-photon single-cell imaging over seven days we show 87% of pericytes constrict during cerebral ischemia, remain constricted post-reperfusion and 50% of the pericyte population are acutely damaged. Moreover, we reveal ischemic pericytes are fundamentally implicated in capillary no-reflow by limiting and arresting blood flow within the first 24 hours post-stroke. Despite sustaining acute membrane damage, we observe up to 80% of cortical pericytes survive ischemia, upregulate unique transcriptomic profiles and replicate. Finally, we demonstrate delayed recovery of capillary diameter by ischemic pericytes after reperfusion predicts vessel reconstriction in the sub-acute phase of stroke. Cumulatively, these findings demonstrate surviving cortical pericytes remain both viable and promising therapeutic targets to counteract no-reflow after ischemic stroke.

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Shrouder, J. J., Filser, S., Varga, D. P., Mamrak, U., Besson-Girard, S., Bulut-Impraim, B., Seker, F. B., Gesierich, B., Laredo, F., Wehn, A. C., Khalin, I., Bayer, P., Liesz, A., Gokce, O., Plesnila, N.. 2023-03-08. Continued dysfunction of capillary pericytes promotes no-reflow after experimental stroke in vivo. https://doi.org/10.1101/2023.03.06.531258

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