Mural Cell SRF Controls Pericyte Migration, Vessel Patterning and Blood Flow.

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.