Extracellular matrix, inflammation, and the angiogenic response

Abstract

Inflammation and angiogenesis are frequently coupled in pathological situations such as atherosclerosis, diabetes, and arthritis. The inflammatory response increases capillary permeability and induces endothelial activation, which, when persistent, results in capillary sprouting. This inflammation-induced angiogenesis and the subsequent remodelling steps are in large part mediated by extracellular matrix (ECM) proteins and proteases. The focal increase in capillary permeability is an early consequence of inflammation, and results in the deposition of a provisional fibrin matrix. Subsequently, ECM turnover by proteases permits an invasive program by specialized endothelial cells whose phenotype can be regulated by inflammatory stimuli. ECM activity also provides specific mechanical forces, exposes cryptic adhesion sites, and releases biologically active fragments (matrikines) and matrix-sequestered growth factors, all of which are critical for vascular morphogenesis. Further matrix remodelling and vascular regression contribute to the resolution of the inflammatory response and facilitate tissue repair.

Figure 1

Progressive steps in inflammation-driven angiogenesis. (1) Quiescent vasculature. (2) Inflammation induced by systemic or local sources activates the angiogenic program by increasing vessel permeability and destabilizing EC junctions. (3) Proteolysis of the ECM by the endothelial tip cell during capillary sprouting induced by inflammatory stimuli. (4) ECM-driven mechanical forces, ECM-derived cryptic sites and matrikines, and growth factor signals during inflammation-mediated angiogenesis. Inflammation-induced angiogenesis can have two distinct fates: 4.1, persistence of vasculature and chronic inflammation and 4.2, vascular regression and tissue repair.

Figure 2

Responsiveness of distinct EC types to inflammatory and angiogenic agents. Soluble factors secreted by inflammatory, accessory, and ECs affect the fate of the different EC types in the sprout (phalanx, stalk, and tip cells), and in particular regulate the induction and specification of tip cells and therefore of capillary sprouting (adapted from De Smet et al.).

Figure 3

Crosstalk between inflammation, endothelial tip cells, and MT1-MMP. Tip cells can be induced by distinct inflammatory pathways (TNFα, bradykinin, NF-κB, and S-1-P) that converge on Rac1 activation and actin polymerization. MT1-MMP expression is restricted to the tip cells. Several inflammatory mediators (nitric oxide, PGE₂, and CCL2/MCP-1) induce MT1-MMP clustering and activity, probably through the activation of Rac1 and actin polymerization, thereby inducing the endothelial tip cell-like phenotype.^–

Figure 4

Schematic representation of VEGF. Two monomers are held together in an anti-parallel orientation by disulfide bonds. The central region (blue) is the receptor binding domain, which binds both VEGFR1 and 2, and is encoded by exons 2–5. The C-terminal region (green) includes the matrix-binding motif (encoded by a variable number and combination of exons 6a, 6b, and 7). Amino acids encoded by exon 8 are present in all VEGF forms. Plasmin and some matrix metalloproteases can sever (by proteolysis) the receptor-binding motif from the extracellular matrix binding domain. Soluble VEGF lacks the matrix-binding region either because it is secreted as a short alternative spliced form (VEGF120) or because is modified post-translationally by plasmin or MMPs. The effects of soluble and bound forms are indicated on the right and based on our previous data.^,