CCL2 promotes proliferation, migration and angiogenesis through the MAPK/ERK1/2/MMP9, PI3K/AKT, Wnt/β‑catenin signaling pathways in HUVECs

Abstract

Severe bone trauma can lead to poor or delayed bone healing and nonunion. Bone regeneration is based on the interaction between osteogenesis and angiogenesis. Angiogenesis serves a unique role in the repair and remodeling of bone defects. Monocyte chemoattractant protein-1, also known as CC motif ligand 2 (CCL2), is a member of the CC motif chemokine family and was the first human chemokine to be revealed to be an effective chemokine of monocytes. However, its underlying mechanism in angiogenesis of bone defect repair remains to be elucidated. Therefore, the present study investigated the detailed mechanism by which CCL2 promoted angiogenesis in bone defects based on cell and animal model experiments. In the present study, CCL2 promoted proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. Western blot analysis revealed that treatment of HUVECs with CCL2 upregulated the protein expression levels of rho-associated coiled-coil-containing protein kinase (Rock)1, Rock2, N-cadherin, c-Myc and VEGFR2. Furthermore, CCL2 promoted the expression of MAPK/ERK1/2/MMP9, PI3K/AKT and Wnt/β-catenin signaling pathway-related proteins, which also demonstrated that CCL2 promoted these functions in HUVECs. Immunohistochemical staining of Sprague Dawley rat femurs following bone defects revealed that VEGF expression was positive in the newly formed bone area in each group, while the expression area of VEGF in the CCL2 addition group was markedly increased. Therefore, CCL2 is a potential therapeutic approach for bone defect repair and reconstruction through the mechanism of angiogenesis-osteogenesis coupling.

Molecular mechanism of anticancer effect of heat shock protein 90 inhibitor BIIB021 in human bladder cancer cell line

“…ANGPT1 is crucial for newly formed blood vessels whereas ANGPT2 destabilizes existing blood vessels for the generation of new blood vessels in collaboration with VEGF (Huang et al 2010 ). In cancer cells, aberrant expression of CCL2 promotes angiogenesis with activation of proliferation, migration, and tube formation in human umbilical vein endothelial cells (Peng et al 2022 ). FLT1 stimulates tumor growth and metastasis, and it is an important biological target for antiangiogenic drug discovery (Shibuya 2011 ).…”

Roles of telocytes dominated cell–cell communication in fibroproliferative acute respiratory distress syndrome

“…104 TGF-β can induce SMAD-dependent (canonical feedback) or SMAD-independent (non-canonical feedback) to moderate non-canonical signalling responses through the WNT, PI3K/AKT, Mitogen-activated protein kinase (MAPK) pathways. [105][106][107] During inflammation, TGF-β has two important functions, including the promotion of wound healing and suppression of inflammation. 108 However, TGF-β stimulates the activation and prolifer-ation of fibroblasts, which result in ECM deposition.…”

“…TGF‐β plays multiple homeostatic roles in the regulation of inflammation, proliferation, differentiation and wound healing of various tissues 104 . TGF‐β can induce SMAD‐dependent (canonical feedback) or SMAD‐independent (non‐canonical feedback) to moderate non‐canonical signalling responses through the WNT, PI3K/AKT, Mitogen‐activated protein kinase (MAPK) pathways 105–107 . During inflammation, TGF‐β has two important functions, including the promotion of wound healing and suppression of inflammation 108 .…”

Extracellular Vesicles’ Role in Angiogenesis and Altering Angiogenic Signaling

“…Additionally, the EVs possess β1 integrin, a surface component that initiates the Rac1-ERK1/2-ETS1 signaling cascade. This process triggers the enhanced release of CCL2, which is known to promote human endothelial cell proliferation, migration, and angiogenesis [ 4 , 99 ]. EVs also carry the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) complex, which prompts angiogenesis by generating plasmin [ 4 ].…”