Requisite Role of p38 MAPK in Mural Cell Recruitment during Angiogenesis in the Rat Aorta Model

Abstract

During the early stage of angiogenesis, neovascular sprouts are composed primarily of endothelial cells. As they mature, microvessels acquire a coating of mural cells, which are critical for the development and maintenance of a functional vasculature. Though growth factor regulation of mural cell recruitment has been extensively investigated, the intracellular signaling events involved in this process remain poorly understood. Among the intracellular kinases implicated in angiogenesis, the p38 MAPK has been shown to transduce signals critical for vascular remodeling and maturation. The rat aorta model of angiogenesis was used to further investigate the role of this signaling pathway in the recruitment of mural cells during angiogenesis. The p38 MAPK inhibitor SB203580 selectively blocked mural cell recruitment, resulting in the formation of naked endothelial tubes without mural cells. SB203580 inhibited angiopoietin-1-induced mural cell recruitment without influencing angiopoietin-1-stimulated endothelial sprouting. Adenoviral vector-mediated expression of a dominant negative form of p38 MAPK significantly reduced mural cell recruitment, whereas overexpression of a constitutively activated form of MKK6, an upstream activator of p38 MAPK, increased mural cell number. These results indicate that the p38 MAPK signaling pathway plays a critical role in mural cell recruitment during neovascularization and may represent a therapeutic target in angiogenesis-related disorders.

LY2228820 Dimesylate, a Selective Inhibitor of p38 Mitogen-activated Protein Kinase, Reduces Angiogenic Endothelial Cord Formation in Vitro and in Vivo

“…p38 MAPK signaling has also been implicated in the regulation of endothelial and mural cell migration (37,38) and recruitment during angiogenesis (11). Inhibition of p38 MAPK led to reduced HSP27 phosphorylation, actin reorganization, and endothelial cell migration (18), which was dependent on MK2 following VEGF stimulation (26).…”

“…In addition to endothelial cells, pericytes play an important role in endothelial cell function and vascular formation (10,11). Pericytes have been associated mainly with stabilization of blood vessels but also can sense angiogenic stimuli, guide sprouting tubes, elicit endothelial survival, and exhibit macrophage-like activities (31).…”

“…Endothelial cells and pericytes communicate via cytokine signaling, and pericytes play a role in maintaining the integrity of endothelial cells by serving as support structures (14). In addition to vascular stabilization, pericytes are important for modulation of endothelial cell migration, proliferation, and survival (11,15). Previous findings suggest a role for p38 MAPK in modulating tumor angiogenesis in tumor cells and/or host endothelial cells (7, 16 -20), but this potential role is not well defined.…”

Identification of chemerin receptor (ChemR23) in human endothelial cells: Chemerin-induced endothelial angiogenesis

“…p38 MAPKinase and ERK 1/2 activition MAPK signalling pathways are involved in EC proliferation and specifically, p38 MAPK signalling has been documented to be critically involved in endothelial angiogenesis [16]. We investigated transient phosphorylation of p38 MAPK in EC lysates treated with both time (0-30 minutes) and dose (0-30nM) dependent chemerin.…”

Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells

“…As neovessel outgrowths are largely enveloped by mural cells in ex vivo models (Gerhardt et al, 2003;Zhu et al, 2002) (supplementary material Fig. S3), we considered the possibility that interactions of pericytes, vascular smooth muscle cells (VSMCs) and endothelial cells participate in regulating MT1-MMP expression.…”