Abstract
Bone marrow (BM)-derived stem/progenitor cells play an important role in ischemia-induced angiogenesis in cardiovascular diseases. Heat shock factor 1 (HSF1) is known to be induced in response to hypoxia and ischemia. We examined whether HSF1 contributes to ischemia-induced angiogenesis through the mobilization and recruitment of BM-derived stem/progenitor cells using HSF1-knockout (KO) mice. After the induction of ischemia, blood flow and microvessel density in the ischemic hindlimb were significantly lower in the HSF1-KO mice than in the wild-type (WT) mice. The mobilization of BM-derived Sca-1- and c-kit-positive cells in peripheral blood after ischemia was significantly lower in the HSF1-KO mice than in the WT mice. BM stem/progenitor cells from HSF1-KO mice showed a significant decrease in their recruitment to ischemic tissue and in migration, adhesion, and survival when compared with WT mice. Blood flow recovery in the ischemic hindlimb significantly decreased in WT mice receiving BM reconstitution with donor cells from HSF1-KO mice. Conversely, blood flow recovery in the ischemic hindlimb significantly increased in HSF1-KO mice receiving BM reconstitution with donor cells from WT mice. These findings suggest that HSF1 contributes to ischemia-induced angiogenesis by regulating the mobilization and recruitment of BM-derived stem/progenitor cells.
Highlights
Angiogenesis in response to ischemia, including the sprouting of new capillary branches from pre-existing vessels, is an adaptive response in tissues with compromised blood supply, and it is important for perfusion after critical ischemia [1,2,3]
We found that the vascular endothelial growth factor (VEGF) levels in the plasma and limb tissue in the Heat shock factor 1 (HSF1)-KO mice increased after inducing limb ischemia (Figure 2A and 2B), and that VEGF levels in the plasma and ischemic tissue did not significantly differ between HSF1-KO and WT mice 3 days after ischemia
Our study provides the first evidence that HSF1 plays a pivotal role in ischemia-induced neovascularization by regulating the mobilization and recruitment of bone marrow (BM)-derived stem/progenitor cells
Summary
Angiogenesis in response to ischemia, including the sprouting of new capillary branches from pre-existing vessels, is an adaptive response in tissues with compromised blood supply, and it is important for perfusion after critical ischemia [1,2,3]. The stem/progenitor cells in BM are mobilized into the peripheral blood in response to ischemia and are recruited to the sites of ischemic injury to contribute to neovascularization, promoting blood flow recovery [4,5,6,7]. The mobilization and recruitment of BM-derived stem/progenitor cells are critical in ischemia-induced neovascularization. Recent studies have shown that HSP90 or heme oxygenase-1 (HSP32), one of the target molecules of HSF1, may contribute to neovascularization after hindlimb ischemia [13,14,15]. Given that the expression of HSPs is mainly regulated by HSF1, it is possible that HSF1 regulates the mobilization and recruitment of BM-derived stem/progenitor and contributes, at least in part, to angiogenesis in response to ischemia
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