Mechanisms in the loss of capillaries in systemic sclerosis: angiogenesis versus vasculogenesis

Abstract

Systemic sclerosis (SSc, scleroderma) is a chronic, multisystem connective tissue disorder affecting the skin and various internal organs. Although the disease is characterized by a triad of widespread microangiopathy, fibrosis and autoimmunity, increasing evidence indicates that vascular damage is a primary event in the pathogenesis of SSc. The progressive vascular injury includes persistent endothelial cell activation/damage and apoptosis, intimal thickening, delamination, vessel narrowing and obliteration. These profound vascular changes lead to vascular tone dysfunction and reduced capillary blood flow, with consequent tissue ischemia and severe clinical manifestations, such as digital ulceration or amputation, pulmonary arterial hypertension and scleroderma renal crisis. The resulting tissue hypoxia induces complex cellular and molecular mechanisms in the attempt to recover endothelial cell function and tissue perfusion. Nevertheless, in SSc patients there is no evidence of significant angiogenesis and the disease evolves towards chronic tissue ischemia, with progressive and irreversible structural changes in multiple vascular beds culminating in the loss of capillaries. A severe imbalance between pro-angiogenic and angiostatic factors may also lead to impaired angiogenic response during SSc. Besides insufficient angiogenesis, defective vasculogenesis with altered numbers and functional defects of bone marrow-derived endothelial progenitor cells may contribute to the vascular pathogenesis of SSc. The purpose of this article is to review the contribution of recent studies to the understanding of the complex mechanisms of impaired vascular repair in SSc. Indeed, understanding the pathophysiology of SSc-associated vascular disease may be the key in dissecting the disease pathogenesis and developing novel therapies. Either angiogenic or vasculogenic mechanisms may potentially become in the future the target of therapeutic strategies to promote capillary regeneration in SSc.

Fig 1

Mechanisms of impaired angiogenesis in SSc. A complex imbalance between pro-angiogenic and anti-angiogenic (angiostatic) mediators results in an impaired and decreased ability to form new microvessels. This leads to the formation of enlarged, giant and bushy capillaries, microhaemorrhages and avascular areas (vascular desertification) as shown by nailfold capillaroscopy. See text for abbreviations.

Fig 2

MMP-12-dependent cleavage of uPAR in SSc microvascular endothelial cells (MVECs) results in impaired angiogenesis. uPAR is a glycosylphosphatidylinositol-anchored 3-extracellular domain (D1-D2-D3) cell surface receptor that concentrates the serine protease activity of the uPA in the pericellular region and promotes extracellular matrix remodelling. The main binding site for uPA is located in D1, and interaction of uPA and uPAR activates the proteolytic cascade necessary to open a path within tissues to migrating cells. Moreover, uPAR not only functions as uPA receptor but also plays a role in growth factor activation, cell adhesion, differentiation, proliferation and migration by interacting with extracellular matrix molecules, including vitronectin (VN), and intracellular signalling mediators, such as the integrin receptors. VN/uPAR interaction occurs directly with D1, but requires the integrity of the full-length receptor (D1-D2-D3). The removal of D1 also abolishes the interaction of uPAR with integrins and its ability to regulate the integrin adhesive functions. The constitutive overproduction and secretion of MMP-12 by SSc dermal MVECs and fibroblasts accounts for endothelial cell uPAR cleavage between D1 and D2, leaving a truncated receptor (D2-D3) on MVEC surface which results in loss of an integrin-mediated uPAR connection with the actin cytoskeleton. The uncoupling of cleaved uPAR from integrins impairs the activation of Rac and Cdc42, thus inhibiting their ability to bind the p21-activated protein kinase 1 (PAK-1), which regulates the downstream signalling cascades of small Rho GTPases and the uPAR-dependent cytoskeletal rearrangement. The net result is the impairment of cell proliferation, migration, invasion, and tube formation, thus preventing SSc MVECs from entering a suitable angiogenic programme in vitro. See text for abbreviations.

Fig 3

Mechanisms of impaired vasculogenesis in SSc. Different scenarios may be responsible for the altered numbers and defective vascular repair ability of bone marrow-derived CD34⁺/CD133⁺/VEGFR-2⁺ EPCs and MSCs in SSc. Aside from haemangioblast-derived CD34⁺ EPCs, there is evidence that MSCs may also differentiate into EPCs. VEGF and SDF-1 are oxygen-sensitive cytokines that are induced by hypoxia, and act as molecular mediators to rapidly mobilize EPCs from the bone marrow and to guide them into ischemic tissues. Besides VEGF and SDF-1, other cytokines and growth factors, such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO), are also important for the maturation and mobilization of bone marrow resident CD34⁺ EPCs. See text for abbreviations.