Klf4 has an unexpected protective role in perivascular cells within the microvasculature

Recent smooth muscle cell (SMC) lineage tracing studies have revealed SMCs undergo remarkable changes in phenotype during development of atherosclerosis. Of major interest, we demonstrated that KLF4 in SMC is detrimental for overall lesion pathogenesis in that SMC-specific conditional knockout of Klf4 resulted in smaller, more stable lesions that exhibited marked reductions in the numbers of SMC-derived macrophage-like and mesenchymal stem cell-like cells. However, since the clinical consequences of atherosclerosis typically occur well after our reproductive years, we sought to identify beneficial KLF4-dependent SMC functions that were likely to be evolutionarily conserved. Herein we tested the hypothesis that Klf4-dependent SMC transitions play an important role in tissue injury-repair. Utilizing SMC-specific lineage tracing mice +/- simultaneous SMC-specific conditional knockout of Klf4, we demonstrate that SMCs in the remodeling heart following ischemia-reperfusion injury (IRI) express KLF4 and transition to a Klf4-dependent macrophage-like state and a Klf4-independent myofibroblast-like state. Moreover, SMC-Klf4 knockout mice had exacerbated heart failure following IRI. Surprisingly, we observed significant cardiac dilation in SMC-Klf4 knockout mice prior to IRI, as well as a reduction in peripheral resistance. KLF4 ChIP-Seq analysis on mesenteric vascular beds identified potential baseline SMC KLF4 target genes in numerous pathways including PDGF and FGF. Moreover, microvascular tissue beds in SMC-Klf4 knockout mice had gaps in lineage traced SMC coverage along the resistance arteries and exhibited increased permeability. Taken together, these results provide novel evidence that Klf4 has a critical maintenance role within microvascular SMCs, including being required for normal SMC function and coverage of resistance arteries.