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

Recent smooth muscle cell (SMC) lineage tracing studies have demonstrated that SMCs undergo remarkable changes in phenotype during development of atherosclerosis, including loss of typical SMC markers such as ACTA2 and Klf4 dependent activation of multiple markers of macrophages and mesenchymal stem cells. Of major interest, we showed Klf4 in SMC is critical for overall lesion pathogenesis as SMC-specific conditional knockout (KO) 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. Herein we tested the hypothesis that Klf4 dependent SMC transitions are beneficial following myocardial infarction (MI). Utilizing SMC-specific lineage tracing mice +/- simultaneous SMC-specific conditional KO of Klf4, we demonstrate that SMCs express Klf4 and transition to a Klf4 dependent macrophage-like state as well as a Klf4 independent myofibroblast-like state. SMC specific, conditional KO of Klf4 resulted in marked exacerbation of heart failure following MI. Surprisingly, significant cardiac dilation was seen in SMC-Klf4 KO mice prior to MI. This cardiac dilation was accompanied by a reduction in peripheral resistance, as evidenced by a reduction in blood pressure, an increase in blood flow, and a larger passive diameter of mesenteric resistance arteries as measured by pressure myography. Klf4 ChIP-Seq analysis on the mesenteric resistance arteries identified potential Klf4 target genes in SMC at baseline in pathways including PDGF and FGF signaling previously shown to be important for perivascular cell investment. Interestingly, examination of microvascular tissue beds revealed gaps in lineage traced SMC coverage along the resistance arteries. Taken together, these results provide novel evidence that Klf4 has a critical maintenance role within microvascular SMCs, including being required for normal SMC coverage of resistance arteries as well as their function. Overall design: Examination of Klf4 transcription factor at base line in micro-vessels