Vascular Disease in Scleroderma: Angiogenesis and Vascular Repair

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Vascular abnormalities are one of the primary pathologic components of scleroderma. An early vascular indicator is aberrant nail fold capillaries that appear to undergo a switch from a pro- to anti-angiogenic process. Later in the disease process, ineffective and aberrant wound healing becomes apparent with frequent and widespread fibrosis. Pulmonary hypertension, largely due to the loss of pulmonary arterial vasculature, is frequently observed in late stages of the disease. The common theme of all these processes is abnormal regeneration of the vasculature and ongoing vascular losses due to defective maintenance of the vasculature. Although most aspects of vascular injury in scleroderma are poorly understood, certain biologic themes are beginning to emerge that are important in understanding scleroderma-related vascular disease.

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Bone marrow–derived cells in systemic sclerosis vascular repair

Certain subsets of bone marrow–derived mononuclear cells are thought to home to sites of vascular injury and ischemia where they cooperate with existing endothelial cells in vascular healing [8]. Some investigators have considered that SSc patients may have abnormal levels of these bone marrow–derived cell populations that impact the replacement of damaged endothelial cells in ischemic or injured tissue. For example, SSc patients with more advanced disease have fewer circulating CD133+ and

The pro- to anti-angiogenic switch

One of the earliest vascular abnormalities observed in scleroderma is Raynaud's phenomenon. In the early stages of the disease, microscopic analysis of the nail fold beds demonstrates the presence of tortuous, giant capillary loop clusters that are surrounded by normal capillary loops of varied shapes with some detectable microhemorrhages, reminiscent of immature newly formed vasculature during an angiogenic response. The short lived pro-angiogenic response is followed by an extensive reduction

Anti-angiogenesis and vascular homeostasis

The presence of widespread angiogenic abnormalities, even in ostensibly uninvolved tissues in SSc patients, suggests the presence of circulating anti-angiogenic factors. Vascular homeostasis requires both pro- and anti-angiogenic factors. The pro-angiogenic factors are secreted molecules that promote endothelial cell proliferation, migration, and tubulogenesis [14], [15]. Many anti-angiogenic molecules are cleavage products of a number of extracellular proteins [16], [17]. The activity of the

Overlapping pathways: hemostasis and angiogenesis

The plasminogen activator pathway and angiogenesis have key roles in wound healing. A prominent feature of SSc is abnormal wound healing in the skin and internal organs that causes scarring and sclerosis [18]. Plasminogen is a precursor of pro-angiogenic plasmin [26] and anti-angiogenic angiostatin [27]; therefore, it has a complicated role in the regulation of vascular homeostasis. Plasminogen can be cleaved at the carboxy terminus by plasminogen activator to produce plasmin, a proteolytic and

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    This work was supported in part by NIH grants HL069948 (MJMK), HL53793, and 62289 (MS), and a grant from the Scleroderma Research Foundation (MS).

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