Abstract 14844: Thsd-1 Determines Plaque Phenotype by Regulating Vascular Permeability and Intraplaque Haemorrhaging
Rationale Neovascularization plays an important role in plaque progression towards a vulnerable plaque (VP). Newly formed intraplaque vasculature shows comprised vessel integrity, rendering them susceptible to extravasation of immune competent cells and erythrocytes, causing increased inflammation and intraplaque haemorrhaging. In a recently performed genome-wide screen we identified Thrombospondin, type 1, domain containing 1 (Thsd-1) as a potential angiogenic factor. In this study we sought to determine the role of Thsd-1 in neovascularization in the VP.
Methods & Results In human carotid endarteriectomy specimens, Thsd-1 expression in endothelial cells is increased in advanced lesions with intraplaque haemorrhaging compared to stable lesions (p<0.05), suggesting the involvement of Thsd-1 in neovascularization. In vitro evaluation of potential causal factors showed that TNFα and low oxygen condition decreased Thsd-1 mRNA and protein expression in HUVECs, demonstrating that these pro-atherogenic factors could decrease Thsd-1 expression. On the contrary, the anti-atherogenic cytokine IL-10 increased Thsd-1 mRNA and protein expression. In a murine VP model, adenoviral transfection of a murine cDNA Thsd-1 expression plasmid protected VP lesions from vascular leakage in the adventitia and intima, as demonstrated by systemic Dextran Fitc injection, compared to sham virus transfected mice (p<0.05). Ter119 immunostaining verified that there was indeed less adventitial (p<0.01) and intimal erythrocyte accumulation (p<0.05). These phenomena were independent of vessel density for there was no difference in intimal or adventitial CD31 positive cells (p=0.5 and 0.15 respectively), suggesting that Thsd-1 influences vessel integrity but not formation. Thsd-1 overexpression also decreased intimal CD68 percentage and necrotic core formation (p<0.05), but did not influence plaque size (p=0.68) or lipid accumulation (p=0.69). Carotid Thsd-1 overexpression in the mouse increased TIMP1 mRNA expression but did not influence TIMP2, MMP2 or MMP9 mRNA levels, indicating vascular protection via a decrease in MMP9 activity.
Conclusion Thsd-1 promotes advanced lesion stability by retaining vascular integrity of the intimal neovasculature.
- © 2011 by American Heart Association, Inc.