Chronic cardiac ischemia/hypoxia induces coronary collateral formation and cardiomyocyte proliferation. Hypoxia can induce cellular adaptive responses, such as synthesis of VEGF for angiogenesis and IGF-2 for proliferation. Both reduce apoptotic effects to minimize injury or damage. To investigate the mechanism of neoangiogenesis and proliferation of embryonic cardiomyocytes under ischemia/hypoxia stress, we used H9c2 embronic cardiomyoblast cell culture, and in vivo embryonic hearts as our study models. Results showed hypoxia induced not only the increase of IGF-2 and VEGF expression but also the activation of its upstream regulatory genes, HIF-1α and Shh. The relationship between HIF-1α and Shh was further studied by using cyclopamine and 2-ME2, inhibitor of Shh and HIF-1α signaling respectively, in the cardiomyocyte cell culture under hypoxia. We found that the two inhibitors not only blocked their own signal pathway, but also inhibited each other. The observations revealed that HIF-1α and Shh pathways may involve in cell proliferation and neoangiogenesis in response to hypoxia of embryonic heart, whereas the complex cross-talk between the two pathways remains unknown.?
