Mural cell SRF controls pericyte migration, vessel patterning and blood flow

Orlich, M. M.; Dieguez-Hurtado, R.; Muehlfriedel, R.; Sothilingam, V.; Wolburg, H.; Oender, C. E.; Woelffing, P.; Betsholtz, C.; Gaengel, K.; Seeliger, M.; Adams, R. H.; Nordheim, A.

doi:10.1101/2021.11.26.470022

bioRxiv · 10.1101/2021.11.26.470022

Mural cell SRF controls pericyte migration, vessel patterning and blood flow

Orlich, M. M.·Dieguez-Hurtado, R.·Muehlfriedel, R.·Sothilingam, V.·Wolburg, H.·Oender, C. E.·Woelffing, P.·Betsholtz, C.·Gaengel, K.·Seeliger, M.·Adams, R. H.·Nordheim, A.

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Abstract

RationalePericytes (PCs) and vascular smooth muscle cells (vSMCs), collectively known as mural cells (MCs), are recruited through PDGFB-PDGFRB signaling. MCs are essential for vascular integrity, and their loss has been associated with numerous diseases. Most of this knowledge is based on studies in which MCs are insufficiently recruited or fully absent upon inducible ablation. In contrast, little is known about the physiological consequences that result from impairment of specific MC functions. ObjectiveHere, we characterize the role of the transcription factor serum response factor (SRF) in MCs and study its function in developmental and pathological contexts. Methods and ResultsWe generated a mouse model of MC-specific inducible Srf gene deletion and studied its consequences during retinal angiogenesis. By postnatal day (P)6, PCs lacking SRF were morphologically abnormal and failed to properly co-migrate with angiogenic sprouts. As a consequence, PC-deficient vessels at the retinal sprouting front became dilated and leaky. By P12, also the vSMCs had lost SRF, which coincided with the formation of pathological arteriovenous (AV) shunts. Mechanistically, we show that PDGFB-dependent SRF activation is mediated via MRTF co-factors. We further show that MRTF-SRF signaling promotes pathological PC activation during ischemic retinopathy. RNA-sequencing, immunohistology, in vivo live imaging and in vitro experiments demonstrated that SRF regulates expression of contractile SMC proteins essential to maintain the vascular tone. ConclusionsSRF is crucial for distinct functions in PCs and vSMCs. SRF directs PC migration downstream of PDGFRB signaling and mediates pathological PC activation during ischemic retinopathy. In vSMCs, SRF is essential for expression of the contractile machinery, and its deletion triggers formation of AV shunts. These essential roles in physiological and pathological contexts provide a rational for novel therapeutic approaches through targeting SRF activity in MCs.

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Orlich, M. M., Dieguez-Hurtado, R., Muehlfriedel, R., Sothilingam, V., Wolburg, H., Oender, C. E., Woelffing, P., Betsholtz, C., Gaengel, K., Seeliger, M., Adams, R. H., Nordheim, A.. 2021-11-27. Mural cell SRF controls pericyte migration, vessel patterning and blood flow. https://doi.org/10.1101/2021.11.26.470022

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