Vascular response to intra-arterial injury in the thrombospondin-1 null mouse

Abstract

Thrombospondin-1 (TSP-1) is a multifunctional, extracellular matrix protein that has been implicated in the regulation of smooth muscle cell proliferation, migration and differentiation during vascular development and injury. Vascular injury in wildtype and TSP-1 null mice was carried out by insertion of a straight spring guidewire into the femoral artery via a muscular arterial branch. Blood flow was restored after the muscular branch was ligated. The injury completely denuded the endothelium and caused medial distension of the vessel in a manner similar to coronary artery balloon-angioplasty. After 28 days, wildtype arteries showed consistent neointima formation with smooth muscle cell hyperplasia. Injured arteries from TSP-1 null mice showed similar neointimal lesions with no significant difference in the extent of neointima formation. Unexpectedly, a high incidence of thrombus formation was observed in the TSP-1 null vessels in a region close to the entry point of the guidewire into the femoral artery. Thrombus was never observed in the injured wildtype vessels. These results provide in vivo evidence that the extent of smooth muscle cell proliferation and neointima formation following endothelial denuding injury is not affected by the absence of TSP-1. Furthermore, our results provide novel evidence for the involvement of TSP-1 in controlling thrombus growth following intra-arterial injury in areas of predicted high turbulent flow.

Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling

“…4,14 The role of endogenous TSP1 in the process of thrombus formation is less clear in severe vessel injury such as those created by guide wire endothelial stripping of arterial segments. 64 Consistent with previous reports that CD47-binding peptides increase platelet aggregation, 10-12 we found that CD47-binding peptides potently antagonize NO-stimulated delays in aggregation. This occurred under high shear and static conditions.…”

Expression Changes of Transforming Growth Factor-Beta1 and Thrombospondin-1 in Cavernous Tissues of Diabetic Rats

“…and is frequently expressed at sites of inflammation and wound healing [14] . In vitro studies have demonstrated that TSP-1 is associated with atherosclerotic lesions, occluded grafts and vascular smooth muscle cell hyperplasia after vascular injury [15] . TSP-1 was also reported to be important in modulating fibrosis.…”

“…TSP-1 is a multifunctional glycoprotein expressed by a variety of cell types, such as platelets, vascular smooth muscle cells, endothelial cells and fibroblasts [14] . Some researches have previously determined that increases in TSP-1 expression could exacerbate vascular injury [15] and fibrotic complications involving the myocardium and mesangial cells [16,17] .…”

Stainless Steel Ions Stimulate Increased Thrombospondin-1-Dependent TGF-Beta Activation by Vascular Smooth Muscle Cells: Implications for In-Stent Restenosis

“…Neointima formation following carotid artery ligation is reduced in TSP1 null mice, with decreased α-SMA-positive cells, but increased collagen and osteopontin deposition [57]. Others observed no difference in vascular response to wire-induced injury between wild-type and TSP1 null mice, but more thrombus formation [58]. Because TSP1 has multiple functions apart from regulation of TGF-β activation, including regulating MMP activity and NO signaling, these null phenotypes might reflect the absence of multiple, sometimes contradictory functions.…”