Kindlin‐2 Deletion in Mural Cells Leads to Vascular Instability

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Abstract
Crucial to homeostasis, vascular barrier function depends upon coordinated interplay between endothelial (ECs) and mural cells, including vascular smooth muscle cells (vSMCs) and pericytes, that stabilize the vasculature. Kindlin‐2 (K2) is an integrin co‐activator regulating various cellular responses, but its role in mural cell‐dependent vascular stabilization is unknown. The role of K2 in mural cell‐mediated regulation of vascular barrier function was investigated. Vascular permeability was assessed in SMC/pericyte‐specific tamoxifen‐inducible K2 knockout ( Fermt2 Δ/Δ Myh11‐CreERT2 + ROSA26‐floxed STOP eYFP +/+ ), lineage tracing mice (K2 Δ/Δ ) and their K2 wild‐type littermates (K2 WT/WT ). In Miles assays, K2 Δ/Δ mice showed increased basal by (20%–75%) and vEGF, PAF, or mustard oil‐induced vascular permeability of Evans blue into the skin (by 2‐ to 3‐fold) compared to K2 WT/WT mice. In LPS‐induced sepsis, vascular leakage into the lungs and liver was 50% higher in K2 Δ/Δ mice than in K2 WT/WT littermates. The enhanced vascular leakiness in K2 Δ/Δ mice was due to aberrant vasculature characterized by decreased coverage with vSMCs. In ex vivo experiments, K2 Δ/Δ aortic vSMCs and brain pericytes had severely reduced β1 and β3 integrin activation, leading to attenuated adhesion to integrin ligands (by ~60%–80%) compared to the K2 WT/WT cells. K2 Δ/Δ vSMCs showed diminished interactions with ECs during endothelial tube formation, dedifferentiation, and enhanced apoptosis. The same effect was observed in human aortic vSMCs upon 50% K2 downregulation with K2‐specific shRNA. In contrast to K2 WT/WT , the K2 Δ/Δ pericytes failed to support barrier formation by brain microvascular ECs in the ex vivo blood–brain barrier model. Together, K2 as an integrin coactivator sustains mural cell functions, contributing to vascular stabilization.
Funding Information
  • National Heart, Lung, and Blood Institute (5P01 HL154811, R01 HL150193)

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