Abstract
CD248 (Endosialin) is a type 1 membrane protein involved in developmental and pathological angiogenesis through its expression on pericytes and regulation of PDGFRβ signalling. Here we explore the function of CD248 in skeletal muscle angiogenesis. Two distinct forms of capillary growth (splitting and sprouting) can be induced separately by increasing microcirculatory shear stress (chronic vasodilator treatment) or by inducing functional overload (extirpation of a synergistic muscle). We show that CD248 is present on pericytes in muscle and that CD248-/- mice have a specific defect in capillary sprouting. In contrast, splitting angiogenesis is independent of CD248 expression. Endothelial cells respond to pro-sprouting angiogenic stimulus by up-regulating gene expression for HIF1α, angiopoietin 2 and its receptor TEK, PDGF-B and its receptor PDGFRβ; this response did not occur following a pro-splitting angiogenic stimulus. In wildtype mice, defective sprouting angiogenesis could be mimicked by blocking PDGFRβ signalling using the tyrosine kinase inhibitor Imatinib mesylate. We conclude that CD248 is required for PDGFRβ-dependant capillary sprouting but not splitting angiogenesis, and identify a new role for CD248 expressed on pericytes in the early stages of physiological angiogenesis during muscle remodelling.
Highlights
Angiogenesis is the physiological process through which new blood vessels are formed from cells of the existing vasculature
Pericytes were identified histologically with a panel of antibodies against platelet-derived growth factor receptor beta (PDGFRb), neuron glial antigen 2 (NG2) and alpha smooth muscle actin (aSMA) and clearly visible under the collagen IV basement membrane in close association with CD31positive capillaries (Figure 1A). In both WT and CD248-/- tissue almost all CD31 positive vessels within the skeletal muscle (.90%) were associated with pericyte cell bodies or processes (Figure 1C) expressing a heterogeneous mix of PDGFRb, NG2 and aSMA (Figure 1D), confirming previous studies demonstrating that pericyte processes cover 99% of capillary length in normal skeletal muscle [6]
CD248 was visible on some of these pericytes (Figure 1B, examples marked with a star) and occasionally on cells where none of the three other pericyte markers used were detectable (Figure 1B, example marked with an arrow)
Summary
Angiogenesis is the physiological process through which new blood vessels are formed from cells of the existing vasculature. This can be achieved by one of two processes, splitting or sprouting, that require different levels of pericyte involvement (reviewed in [1,2]). Pericytes are a heterogeneous population of perivascular cells located in close proximity to endothelial cells beneath a common basement membrane [2,6,7]. Pericytes are defined as cells expressing either platelet-derived growth factor receptor beta (PDGFRb), neuron glial antigen 2 (NG2), alpha smooth muscle actin (aSMA) or CD248 (endosialin) in close proximity to CD31 positive endothelial cells (reviewed in [1,8])
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