Thrombospondin-4 regulates vascular inflammation and atherogenesis.
BACKGROUND
Thrombospondin (TSP)-4 is an extracellular protein that has been linked to several cardiovascular pathologies. However, a role for TSP-4 in vascular wall biology remains unknown.


OBJECTIVE
We have examined the effects of TSP-4 gene (Thbs4) knockout on the development of atherosclerotic lesions in ApoE(-/-) mice.


RESULTS
Deficiency in TSP-4 reduced atherosclerotic lesions: at 20 weeks of age, the size of the aortic root lesions in Thbs4(-/-)/ApoE(-/-) mice was decreased by 48% in females and by 39% in males on chow diets; in mice on Western diets, lesions in the descending aorta were reduced by 30% in females and 33% in males. In ApoE(-/-) mice, TSP-4 was abundant in vessel areas prone to lesion development and in the matrix of the lesions themselves. TSP-4 deficiency reduced the number of macrophages in lesions in all groups by ≥ 2-fold. In addition, TSP-4 deficiency reduced endothelial cell activation (expression of surface adhesion molecules) and other markers of inflammation in the vascular wall (decreased production of monocyte chemoattractant protein-1 and activation of p38). In vitro, both the adhesion and migration of wild-type macrophages increased in the presence of purified recombinant TSP-4 in a dose-dependent manner (up to 7- and 4.7-fold, respectively). These responses led to p38-MAPkinase activation and were dependent on β(2) and β(3) integrins, which recognize TSP-4 as a ligand.


CONCLUSIONS
TSP-4 is abundant in atherosclerotic lesions and in areas prone to development of lesions and may influence the recruitment of macrophages by activating endothelial cells and directly interacting with macrophages to increase their adhesion and migration. Our observations suggest an important role for this matricellular protein in the local regulation of inflammation associated with atherogenesis.
Frolova
Ella G
EG
Department of Molecular Cardiology and Joseph J. Jacob Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Ohio 44195, USA.
Pluskota
Elzbieta
E
Krukovets
Irene
I
Burke
Tim
T
Drumm
Carla
C
Smith
Jonathan D
JD
Blech
Lauren
L
Febbraio
Maria
M
Bornstein
Paul
P
Plow
Edward F
EF
Stenina
Olga I
OI
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019699:Thrombospondins / Q000172:deficiency / Q000502:physiology*; D014652:Vascular Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
D018836:Inflammation Mediators; D019699:Thrombospondins; C101864:thrombospondin 4