Roles of receptor activity-modifying protein 1 in angiogenesis and lymphangiogenesis during skin wound healing in mice

Receptor activity-modifying protein 1 (RAMP1) forms a complex with calcitonin receptor-like receptor (CLR) to produce the receptor for calcitonin gene-related peptide (CGRP). CGRP, a 37-aa neuropeptide, is widely distributed in neuronal tissues and exerts its biological effects via CLR/RAMP1; however, the pathophysiological roles of CLR/RAMP1 remain to be clarified. To study the functions of CLR/RAMP1, we generated RAMP1-knockout (RAMP1(-/-)) mice. Compared with those of wild-type (WT) mice, wound healing and wound-induced angiogenesis were significantly suppressed in RAMP1(-/-) mice, with reduced expression of vascular endothelial growth factor (VEGF)-A. Formation of the lymphatic vessels that drain interstitial fluids was also suppressed in RAMP1(-/-) mice, with reduced expression of VEGF-C and VEGFR-3 in wound granulation tissues. RAMP1 was expressed in endothelial cells (ECs) in the preexisting skin blood vessels, but was not observed in ECs in newly formed blood or lymphatic vessels. Macrophages in the wound granulation tissues expressed RAMP1 and produced substantial amounts of VEGF-C in response to CGRP in vitro. RAMP1(-/-) bone marrow chimeric mice showed delayed wound healing with reduced angiogenesis/lymphangiogenesis in wound granulation tissues. These findings suggest that RAMP1 plays a crucial role in wound healing and wound-induced angiogenesis and lymphangiogenesis and that it is a promising target for controlling angiogenesis and lymphangiogenesis.