Lack of RAMP1 Signaling Suppresses Liver Regeneration and Angiogenesis Following Partial Hepatectomy in Mice

Background/aim: The liver effectively restores both size and function following partial hepatectomy (PHx). Angiogenesis is crucial for the repair and regeneration of liver tissue post-PHx. Calcitonin gene-related peptide (CGRP) released from sensory nerves and its receptor-receptor activity-modifying protein 1 (RAMP1) are involved in angiogenesis. This study aimed to assess the role of RAMP1 signaling in angiogenesis during liver regeneration following PHx.

Materials and methods: RAMP1 deficient (RAMP1^-/-) and wild-type (WT) mice were subjected to PHx.

Results: RAMP1^-/- mice demonstrated delayed liver regeneration, indicated by lower liver-to-body weight ratios compared to WT mice. This was associated with lower levels of Ki67⁺ hepatocytes and hepatic trophic growth factors. Additionally, RAMP1^-/- mice exhibited lower levels of endothelial cell markers, including CD31, compared to WT mice. This reduction was associated with reduced levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor 3 (VEGFR3). In WT mice with PHx, the administration of a VEGFR3 inhibitor reduced the liver-to-body weight ratio, Ki67⁺ hepatocytes, and VEGF-C/VEGFR3 expression levels in the liver compared to those in the vehicle-treated group.

Conclusion: The deletion of RAMP1 signaling suppresses liver regeneration and angiogenesis through VEGFR3. Specific activation of RAMP1 signaling may represent a potential therapeutic strategy for liver regeneration following PHx.