An ANP-mediated local crosstalk from cardiomyocytes to pericytes drives angiogenesis after myocardial infarction

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Tissue repair after myocardial infarction involves an angiogenic response that starts in the infarct border zone. Here, new capillaries “sprout” from endothelial cells (ECs) and pericytes, stimulated by proangiogenic factors secreted from surrounding hypoxic cells. Unravelling this intercellular communication can help to find novel targets for proangiogenic therapies reducing adverse cardiac remodeling. ANP and BNP are among the first “myokines” induced in ventricular cardiomyocytes in response to ischemia. Their shared guanylyl cyclase A (GC-A) receptor is expressed by microvascular cells, allowing a paracrine crosstalk. To elucidate the role in angiogenesis, we (co)cultured EC and pericytes. ANP concentration-dependently stimulated their proliferation via GC-A/cGMP signalling through distinct downstream pathways. Activation of cGMP-dependent protein kinase I triggers proliferation of EC, while a phosphodiesterase-mediated cGMP-to-cAMP crosstalk activates pericytes. To elucidate the relevance in vivo, we studied postischemic angiogenesis in mice with global or conditional GC-A deletion. In mice with systemic GC-A inactivation, vascular regeneration in response to critical hind limb ischemia was severely impaired. Similar attenuation of ischemic angiogenesis was observed in mice with conditional, either EC- or pericyte-restricted, GC-A deletion. Notably after experimental myocardial infarction, only mice with ablated GC-A in pericytes had a markedly impaired angiogenic response and augmented scarring. ANP and BNP, produced by satellite cells within skeletal muscle and by ventricular myocytes in response to hypoxia, stimulate neoangiogenesis via actions on neighboring EC and/or pericytes. This paracrine communication might be critically involved in coordinating cell viability/regeneration and angiogenesis. Supported by the Deutsche Forschungsgemeinschaft (DFG KU 1037/13-1 and SFB 1525)

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