Analogous Phenotypic Consequences of PDGF-B and PDGFRp Mutagenesis
Several interesting conclusions may be drawn from comparing the various mouse lines that have been generated by mutagenesis at the PDGF-B or PDGFRb loci. Not surprisingly, perhaps, the range of phenotypes that is seen in the two mutant series is similar. Both the ligand and receptor series display a gradual reduction in pericyte density, and a phenotypic outcome ranging from normal (no phenotype in the unchallenged state) to overt pathology in the eye, heart and kidney, with the eye displaying the most profound pathology. Interestingly, the relationship between overall degree of pericyte reduction and the resulting pathology was also similar. Both series produced mutants with pericyte reduction ranging from <50 to >90%, and overt phenotypic changes in the eye appear in mutants with more than 50% reduction in the pericyte density. Thus, substantial pericyte reduction appears to be tolerated in organ development, with most organs (in which pericytes depend on PDGF-B/ PDGFRb signaling) tolerating 50% reduction or more. The exception is the eye, which has the highest known normal pericyte density, suggestive of a critical and perhaps unique function for these cells. Intriguingly, development of many organs, including the brain, can be completed relatively normally, even when there is up to 90% reduction in pericyte density. However, these mice have many signs of brain microvessel dysfunction and pathological responses in the astroglia. When mice with 50% reduction or less are exposed to a pathological challenge, such as glomeru-lonephritis or diabetes, there is an exaggerated pathological microvascular response, however.
Not only pericyte numbers, but also their association with the endothelium seems to matter, as illustrated by the PDGF-B retention deficient mice. Probably, a graded, or directional, presentation of PDGF-B by the endothelial cells is required to ensure that the pericytes become correctly associated with the endothelial cells and their basement membrane. Thus the extracellular compartmentalization of PDGF-B seems to be as important for pericyte recruitment as the formation of gradients or depots of VEGF-A in the guidance of endothelial sprouts [17, 25].
Do the Other PDGF/Receptors Play a Role in the Microvasculature?
No other PDGF/PDGFR member is as strongly implicated in microvascular assembly or function as PDGF-B and PDGFRp. PDGFRa knockouts display defects in the cardiac outflow tract [26, 27] that may relate to a primary defect in the neural crest. Likewise, other neural crest-derived populations of vSMC and pericytes may be affected in the PDGFRa knockouts, particularly in the rostral part of the embryo. Again the critical signaling events involving PDGFRa likely take place before the crest-derived vSMC/ pericyte populations are specified. An additional location where PDGFRa signaling might determine the fate of a progenitor of the vSMC/pericyte population is the kidney. Here, PDGFRa null mutants become progressively depleted of interstitial mesenchymal cells. However, these mutants also partially lack mesangial cells in the kidney glomeruli in spite of the fact that PDGFRb is the dominant receptor in these cells. Thus, it is possible that the mesangial progenitors are in part (or fully) recruited from the PDGFRa positive interstitial mesenchyme .
While PDGF-A and -C signaling through PDGFRa may have indirect effects on microvascular development, the function of PDGF-D remains elusive. The strong similarities between PDGF-B and PDGFRb null mutants may suggest that PDGF-D has no or little effect during development. However, it is possible that PDGF-D serves mainly postnatal functions, and that some of these functions may involve the microvasculature. Detailed expression analysis and genetic ablation of PDGF-D in mice will help answering these questions.
PDGF: Platelet-derived growth factor. Afamily of five dimeric ligands (AA, BB, CC, DD and AB) composed of four constituent chains (A, B, C, D) encoded by different genes. PDGF was originally found in platelets and assumed to exert a wound healing function, but is currently know to be expressed by a multitude of cell types and exert numerous important roles, particularly during organogenesis.
PDGFR: Platelet-derived growth factor receptor. A family of two transmembrane receptors (a and b). They are structurally related receptor tyrosine kinases with 5 extracellular Ig domains and a split intracellular kinase domain. The PDGFRs dimerize upon ligand binding, autophospho-rylated, and thereby engage several classical signaling pathways, including
Pericyte: A mural cells of the vessel wall that shares basal lamina with the endothelium. Pericytes are vascular smooth muscle lineage cells that express several of the markers of smooth muscle.
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Dr Christer Betsholtz is professor of Medical Biochemistry at Göteborg University since 1993. His laboratory has explored the physiological roles of the PDGF family members for more than 20 years, which has recently led into the areas of angiogenesis and, in particular, the mechanism of recruitment and function of pericytes. His work is supported by several research councils and foundations in Sweden and Europe.
Dr Holger Gerhardt is a former post doctoral fellow in Betsholtz' group and newly appointed junior group leader at Cancer Research UK, London. His previous work on avian neural development, together with a more recent focus on angiogenesis, has led him into new exciting areas of angio-genic sprout guidance in the central nervous system. He is supported by the Cancer Research UK.
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