Thrombospondin-1 is elevated with both intimal hyperplasia and hypercholesterolemia.
BACKGROUND
Thrombospondin-1 (TSP-1) is important in platelet adhesion and aggregation, inflammation, cell to cell interaction, angiogenesis, and smooth muscle cell (SMC) proliferation. TSP-1 expression increases rapidly with injury. Therefore, we hypothesize that TSP-1 may play a role in the development of intimal hyperplasia (IH). The purpose of this study is to examine the interaction between cholesterol and TSP-1 on SMC proliferation and to quantitatively assess TSP-1 expression in an established model of IH, with and without underlying cholesterol-induced atherosclerosis.


METHODS
In vitro, rabbit aortic SMC culture studies were performed to see the effect of TSP-1 antibodies on PDGF and, separately, cholesterol-induced SMC proliferation. In vivo, 23 rabbits were fed either a regular or a high-cholesterol diet. Hypercholesterolemia was confirmed by measurement of serum levels. Subsets underwent intraluminal aortic injury. Aortas were harvested 8-10 weeks later. Arterial wall TSP-1 was evaluated immunohistochemically and quantified by computer image analysis.


RESULTS
In vitro, TSP-1 antibodies were able to inhibit PDGF and cholesterol-induced SMC proliferation (P < 0.05). In vivo, TSP-1 was found predominantly in the extracellular matrix in the rabbit aorta. IH was uniformly seen status-post angioplasty. Hyperplasia was more prominent in samples from hypercholesterolemic animals. ANOVA and Student's t test analyses demonstrated significantly more TSP-1 in the high-cholesterol/angioplasty group than in all other groups (P = 0.0006 vs regular diet/no angioplasty group).


CONCLUSIONS
These data are consistent with the hypothesis that TSP-1 contributes to the development of IH. This study suggests that injured arteries in hypercholesterolemic atherosclerotic rabbits overexpress TSP-1.
Roth
J J
JJ
Department of Surgery, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania, USA.
Gahtan
V
V
Brown
J L
JL
Gerhard
C
C
Swami
V K
VK
Rothman
V L
VL
Tulenko
T N
TN
Tuszynski
G P
GP
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism*; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011817:Rabbits; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D010982:Platelet-Derived Growth Factor; D019700:Thrombospondin 1