Abstract
Endothelial cells play a critical role in the process of angiogenesis during skin wound healing. The migration and proliferation of endothelial cells are processes that are initiated by the hypoxic microenvironment in a wound, but the underlying mechanisms remain largely unknown. Here, we identified a novel role for microtubule-associated protein 4 (MAP4) in angiogenesis. We firstly demonstrated that MAP4 phosphorylation was induced in hypoxic endothelial cells; the increase in MAP4 phosphorylation enhanced the migration and proliferation of endothelial cells. We also found that hypoxia (2% O2) activated p38/mitogen-activated protein kinase (MAPK) signaling, and we identified p38/MAPK as an upstream regulator of MAP4 phosphorylation in endothelial cells. Moreover, we showed that the promigration and proproliferation effects of MAP4 phosphorylation were attributed to its role in microtubule dynamics. These results indicated that MAP4 phosphorylation induced by p38/MAPK signaling promotes angiogenesis by inducing the proliferation and migration of endothelial cells cultured under hypoxic conditions via microtubule dynamics regulation. These findings provide new insights into the potential mechanisms underlying the initiation of the migration and proliferation of endothelial cells.
Highlights
Endothelial cell (EC) proliferation and migration are essential processes during wound healing, due to their roles in angiogenesis (Munoz-Chapuli et al, 2004; Lamalice et al, 2007; Banyard et al, 2016), which is required to restore oxygen and nutrient supplies (DiPietro, 2013)
Human umbilical vein endothelial cells (HUVECs) and human dermal microvascular endothelial cells (HDMECs) were subjected to hypoxia for 6, 12, or 24 h to determine the effect of hypoxia on ECs
Ethynyl-2 -deoxyuridine (EdU) staining, an advanced method for assessing cell proliferation, revealed a marked increase in the proliferation of HDMECs and HUVECs cultured under hypoxia, as indicated by the positive staining for of 5-ethynyl-2 deoxyuridine (EdU, green) in cell nuclei (Figures 1E,F)
Summary
Endothelial cell (EC) proliferation and migration are essential processes during wound healing, due to their roles in angiogenesis (Munoz-Chapuli et al, 2004; Lamalice et al, 2007; Banyard et al, 2016), which is required to restore oxygen and nutrient supplies (DiPietro, 2013). The hypoxic microenvironment has been proven to be an important initial factor for the healing skin wounds, but the underlying mechanisms remain largely unknown. MAP4, the major MAP protein expressed in non-neuronal mammalian cells, is capable of regulating MT assembly and stability both in vitro and in vivo. The contributions of MAP4 phosphorylation to the proliferation and migration of ECs during angiogenesis remain largely unknown
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