Neural Peptide α-CGRP Coregulated Angiogenesis and Osteogenesis via Promoting the Cross-Talk between Mesenchymal Stem Cells and Endothelial Cells

Abstract

Background. The coupled vascularization and bone remodeling are key steps during bone healing, during which the cross-talk between mesenchymal stem cells (MSCs) and endothelial cells plays vital roles. Evidence indicates the well-characterized neuropeptide Calcitonin Gene-Related Peptide-α (CGRP) is proven to play an important role during bone regeneration. However, the regulatory effects of αCGRP on angiogenesis and osteogenesis, as well as underlying cellular and molecular mechanisms, remain unclear. Aim. The present study was performed to verify the availability of the CGRP for osteogenic capacity in MSCs and explore its potential underlying molecular mechanism. After that, the promoted angiogenic effect of CGRP as well as its underlying mechanisms was studied. Methods and Results. The results showed that CGRP could significantly increase the cyclic adenosine monophosphate (cAMP) level and promote the osteogenesis ability of MSCs via cAMP/PKA signaling pathway. Direct exposure to CGRP increased nitric oxide synthase expression, the release of NO, tube formation, and wound healing of human umbilical vein endothelial cells (HUVEC). The CGRP-treated MSCs were observed with high expression levels of angiogenic factors, such as bFGF and VEGF-α; the conditioned medium derived from CGRP-treated MSCs was also able to promote tube formation and transmembrane migration of HUVECs. Conclusion. These findings demonstrate the coregulated angiogenesis and osteogenesis effects of CGRP, especially for its regulation effects on the cross-talk between mesenchymal stem cells and endothelial cells.

Sensory nerves, but not sympathetic nerves, promote reparative dentine formation after dentine injury via CGRP‐mediated angiogenesis: An in vivo study

“…It is noteworthy that in this study dentine injury evoked an intense in‐growth of newly formed CGRP‐labelled nerve fibres at an early stage, and blocking CGRP signalling led to a reduction in CD31 + vessels and type H vessels, followed by impaired reparative dentine formation. An ex vivo study confirmed that CGRP treatment increases nitric oxide synthase expression, nitric oxide release, and the migratory ability of endothelial cells (Shi et al., 2022). This effect on migration and tube formation of endothelial cells is comparable to that of the known angiogenesis regulator vascular endothelial growth factor (VEGF) (Tuo et al., 2013).…”

Emerging roles of nerve‐bone axis in modulating skeletal system

“…CGRP and SP have already been confirmed as the supportive factors of angiogenesis process 135 . CGRP coupled angiogenesis and osteogenesis by promoting the crosstalk between MSCs and ECs via initiating the cAMP‐signaling pathway 20 . CGRP induces a higher expression level of angiogenic factors, including fibroblast growth factor (FGF) and VEGF.…”

“…16,17 In addition, neural pathways have been found to regulate matrix deposition during skeletal development, which is activated in response to paracrine/autocrine processes. [18][19][20][21][22][23] In turn, bone tissue provides accommodation for peripheral nerves, acts as a scaffold, and actively participates in neuroregulation. Thus, the bone and nerve indeed support each other, implying a neuro-osteogenic network.…”

“…Meanwhile, nerve‐related secretions can also regulate the proliferation of endothelial cells (ECs) and vascularization, constituting the essential source of various growth factors to maintain bone growth and function 16,17 . In addition, neural pathways have been found to regulate matrix deposition during skeletal development, which is activated in response to paracrine/autocrine processes 18–23 …”

Dual Factor-Loaded Artificial Periosteum Accelerates Bone Regeneration

“…CGRP is also a factor that promotes angiogenesis and lymph angiogenesis. − Lin et al encapsulated CGRP in poly­(lactic- co -glycolic acid) (LGA) nanoparticles and found that the release of CGRP could restore the levels of CGRP and vascular inflammatory factors in rats. Gong et al studied the regulatory mechanism of CGRP on angiogenesis and osteogenesis. The results showed that CGRP could significantly increase the level of cyclic adenosine monophosphate (cAMP) in MSCs by regulating the cAMP/PKA signaling pathway and promoting the osteogenic ability of MSCs.…”