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Published on: November 20, 2021
Mural Cell SRF Controls Pericyte Migration, Vessel Patterning and Blood Flow
Michael M Orlich1,2,3,4, Rodrigo Diéguez-Hurtado5,6, Regine Muehlfriedel7
1Department of Molecular Biology, Interfaculty Institute for Cell Biology, University of Tuebingen, Germany (M.M.O., C.E.O., P.W., A.N.).
Background:
Pericytes and vascular smooth muscle cells, collectively known as mural cells, are recruited through PDGFB (platelet-derived growth factor B)-PDGFRB (platelet-derived growth factor receptor beta) 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. Here, we characterize the role of the transcription factor SRF (serum response factor) in MCs and study its function in developmental and pathological contexts.
Methods:
We generated a mouse model of MC-specific inducible Srf gene deletion and studied its consequences during retinal angiogenesis using RNA-sequencing, immunohistology, in vivo live imaging, and in vitro techniques.
Results:
By postnatal day 6, pericytes lacking SRF were morphologically abnormal and failed to properly comigrate with angiogenic sprouts. As a consequence, pericyte-deficient vessels at the retinal sprouting front became dilated and leaky. By postnatal day 12, also the vascular smooth muscle cells had lost SRF, which coincided with the formation of pathological arteriovenous shunts. Mechanistically, we show that PDGFB-dependent SRF activation is mediated via MRTF (myocardin-related transcription factor) cofactors. We further show that MRTF-SRF signaling promotes pathological pericyte 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.
Conclusions:
SRF is crucial for distinct functions in pericytes and vascular smooth muscle cells. SRF directs pericyte migration downstream of PDGFRB signaling and mediates pathological pericyte activation during ischemic retinopathy. In vascular smooth muscle cells, SRF is essential for expression of the contractile machinery, and its deletion triggers formation of arteriovenous shunts. These essential roles in physiological and pathological contexts provide a rationale for novel therapeutic approaches through targeting SRF activity in MCs.
Insights
Serum response factor (SRF) is vital for mural cell migration and vascular integrity. SRF deletion impairs pericyte function, leading to leaky vessels and arteriovenous shunts, suggesting SRF as a therapeutic target.
Area of Science:
- Vascular biology
- Cellular signaling
- Transcriptional regulation
Background:
- Mural cells (MCs), including pericytes and vascular smooth muscle cells, are recruited via PDGFB-PDGFRB signaling and are crucial for vascular integrity.
- Loss of MCs is linked to various diseases, but the consequences of impaired specific MC functions are less understood.
- The role of transcription factor SRF in MCs during development and disease requires further characterization.
Purpose of the Study:
- To investigate the function of serum response factor (SRF) in mural cells (MCs) during vascular development and in pathological conditions.
- To elucidate the mechanisms by which SRF influences pericyte migration and vascular smooth muscle cell function.
Main Methods:
- Generation of a mouse model with inducible, MC-specific deletion of the SRF gene.
- Utilized RNA-sequencing, immunohistology, in vivo live imaging, and in vitro assays to study SRF's role.
- Investigated PDGFB-PDGFRB signaling pathways and MRTF cofactors in SRF activation.
Main Results:
- SRF-deficient pericytes exhibited abnormal morphology and impaired migration, leading to dilated, leaky vessels at the retinal sprouting front.
- Deletion of SRF in vascular smooth muscle cells resulted in the formation of pathological arteriovenous shunts.
- SRF activation by PDGFB is mediated by MRTF cofactors, and MRTF-SRF signaling promotes pathological pericyte activation in ischemic retinopathy.
- SRF regulates the expression of contractile proteins essential for maintaining vascular tone.
Conclusions:
- SRF plays critical, distinct roles in pericytes and vascular smooth muscle cells, governing migration and vascular tone.
- SRF is essential for pericyte migration downstream of PDGFRB signaling and mediates pathological pericyte activation in ischemic retinopathy.
- Targeting SRF activity in MCs presents a potential therapeutic strategy for vascular diseases.
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