PDGFB Pericyte Recruitment and Vessel Maturation

PDGF-B is the most characterized member in the PDGF family. Although first discovered as a secretory product of platelets during coagulation, PDGF-B is also expressed in many other cell types, such as endothelial cells, macrophages, smooth muscle cells, fibroblasts, glial cells, neurons, tumor cells, and possibly others. Expression of PDGF-B is constitutive in immune and nerve cells, whereas inducible expression of PDGF-B most likely occurs in other cell types. The actions of PDGF-B can occur via paracrine and autocrine pathways. PDGF-B is involved in many physiological functions, such as wound healing, inflammation, gestation, and differentiation.

PDGF-B triggers mural cell recruitment to sprouting vessels and proliferation of certain cell types during angiogen-esis. Pericyte recruitment is believed to occur through the secretion of PDGF-B by endothelial cells, stimulating the PDGFR-b on pericytes, leading to migration of these cells to nascent capillaries of the developing microvasculature. In vitro, PDGF-B induces smooth muscle cell migration and proliferation. In addition, PDGF-BB has been shown to increase the expression of PDGFR-b in endothelial cells, eliciting endothelial cell proliferation, resulting in angio-genesis amplification in vitro.

In 1994, two studies revealed the roles of PDGF-B and PDGFR-b in vasculogenesis and angiogenesis during murine development. Soriano demonstrated that PDGFR-b gene knockout impaired kidney development in mice

PDGF Ligands and Receptors

Figure 2 Schematic Representation of the Binding of PDGF Ligands to Their Respective Receptors. PDGF-AA binds only the -aa receptor homodimer. PDGF-BB binds to the -aa and -ab receptors but has the highest binding affinity for the -bb receptor. PDGF-AB preferentially binds to -aa and -ab receptors. PDGF-CC and PDGF-DD interact with the -aa and -bb receptors, respectively. The binding of PDGF to the extracellular immunoglobulin-like domains of its cognate receptors induces receptor homo- or heterodimerization, stimulating tyrosine phosphorylation in the intracellular kinase domains. The phosphorylated tyrosines trigger downstream signaling events to occur cellular events such as mitogenesis, chemotaxis, and apoptosis. (-Y, tyrosine residues) (see color insert)

Figure 2 Schematic Representation of the Binding of PDGF Ligands to Their Respective Receptors. PDGF-AA binds only the -aa receptor homodimer. PDGF-BB binds to the -aa and -ab receptors but has the highest binding affinity for the -bb receptor. PDGF-AB preferentially binds to -aa and -ab receptors. PDGF-CC and PDGF-DD interact with the -aa and -bb receptors, respectively. The binding of PDGF to the extracellular immunoglobulin-like domains of its cognate receptors induces receptor homo- or heterodimerization, stimulating tyrosine phosphorylation in the intracellular kinase domains. The phosphorylated tyrosines trigger downstream signaling events to occur cellular events such as mitogenesis, chemotaxis, and apoptosis. (-Y, tyrosine residues) (see color insert)

because of glomerular development irregularities secondary to an absence of mesangial cells, cells that are structurally and functionally related to pericytes. In addition, hematologic abnormalities such as anemia, thrombocytopenia, erythroblastosis, and arteriolar dilation were also present. The other study performed by Betsholtz and group utilized PDGF-B-deficient mice that displayed a similar phenotype and died perinatally as a result of hemorrhage. In 1997, the effects of PDGF-B deficiency were further characterized, indicating that lack of pericytes during vessel growth produces microvascular aneurysms and related these findings to possible pathological complications seen in diabetes mellitus. These studies demonstrated the importance of PDGF-B signal-ing through the PDGF-b receptor in promoting the recruitment of pericytes to developing vessels thereby increasing their stability.

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