Thrombospondin-1 (TSP1) contributes to the development of vascular inflammation by regulating monocytic cell motility in mouse models of abdominal aortic aneurysm.
BACKGROUND
Histological examination of abdominal aortic aneurysm (AAA) tissues demonstrates extracellular matrix destruction and infiltration of inflammatory cells. Previous work with mouse models of AAA has shown that anti-inflammatory strategies can effectively attenuate aneurysm formation. Thrombospondin-1 is a matricellular protein involved in the maintenance of vascular structure and homeostasis through the regulation of biological functions, such as cell proliferation, apoptosis, and adhesion. Expression levels of thrombospondin-1 correlate with vascular disease conditions.


OBJECTIVE
To use thrombospondin-1-deficient (Thbs1(-/-)) mice to test the hypothesis that thrombospondin-1 contributes to pathogenesis of AAAs.


RESULTS
Mouse experimental AAA was induced through perivascular treatment with calcium phosphate, intraluminal perfusion with porcine elastase, or systemic administration of angiotensin II. Induction of AAA increased thrombospondin-1 expression in aortas of C57BL/6 or apoE-/- mice. Compared with Thbs1(+/+) mice, Thbs1(-/-) mice developed significantly smaller aortic expansion when subjected to AAA inductions, which was associated with diminished infiltration of macrophages. Thbs1(-/-) monocytic cells had reduced adhesion and migratory capacity in vitro compared with wild-type counterparts. Adoptive transfer of Thbs1(+/+) monocytic cells or bone marrow reconstitution rescued aneurysm development in Thbs1(-/-) mice.


CONCLUSIONS
Thrombospondin-1 expression plays a significant role in regulation of migration and adhesion of mononuclear cells, contributing to vascular inflammation during AAA development.
From the Departments of Surgery (Z.L., S.M., J.R., Q.W., B.L.), Pathology and Laboratory Medicine (B.L.), Biomolecular Chemistry and Medicine (D.S.A., D.F.M.), McArdle Laboratory for Cancer Research (J.Z.), Pediatrics (C.M.S.), and Ophthalmology and Visual Sciences (N.S.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (Z.L.).
Zhenjie
Z
Liu
From the Departments of Surgery (Z.L., S.M., J.R., Q.W., B.L.), Pathology and Laboratory Medicine (B.L.), Biomolecular Chemistry and Medicine (D.S.A., D.F.M.), McArdle Laboratory for Cancer Research (J.Z.), Pediatrics (C.M.S.), and Ophthalmology and Visual Sciences (N.S.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (Z.L.).
Stephanie
S
Morgan
From the Departments of Surgery (Z.L., S.M., J.R., Q.W., B.L.), Pathology and Laboratory Medicine (B.L.), Biomolecular Chemistry and Medicine (D.S.A., D.F.M.), McArdle Laboratory for Cancer Research (J.Z.), Pediatrics (C.M.S.), and Ophthalmology and Visual Sciences (N.S.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (Z.L.).
Jun
J
Ren
From the Departments of Surgery (Z.L., S.M., J.R., Q.W., B.L.), Pathology and Laboratory Medicine (B.L.), Biomolecular Chemistry and Medicine (D.S.A., D.F.M.), McArdle Laboratory for Cancer Research (J.Z.), Pediatrics (C.M.S.), and Ophthalmology and Visual Sciences (N.S.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (Z.L.).
Qiwei
Q
Wang
From the Departments of Surgery (Z.L., S.M., J.R., Q.W., B.L.), Pathology and Laboratory Medicine (B.L.), Biomolecular Chemistry and Medicine (D.S.A., D.F.M.), McArdle Laboratory for Cancer Research (J.Z.), Pediatrics (C.M.S.), and Ophthalmology and Visual Sciences (N.S.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (Z.L.).
Douglas S
DS
Annis
From the Departments of Surgery (Z.L., S.M., J.R., Q.W., B.L.), Pathology and Laboratory Medicine (B.L.), Biomolecular Chemistry and Medicine (D.S.A., D.F.M.), McArdle Laboratory for Cancer Research (J.Z.), Pediatrics (C.M.S.), and Ophthalmology and Visual Sciences (N.S.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (Z.L.).
Deane F
DF
Mosher
From the Departments of Surgery (Z.L., S.M., J.R., Q.W., B.L.), Pathology and Laboratory Medicine (B.L.), Biomolecular Chemistry and Medicine (D.S.A., D.F.M.), McArdle Laboratory for Cancer Research (J.Z.), Pediatrics (C.M.S.), and Ophthalmology and Visual Sciences (N.S.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (Z.L.).
Jing
J
Zhang
From the Departments of Surgery (Z.L., S.M., J.R., Q.W., B.L.), Pathology and Laboratory Medicine (B.L.), Biomolecular Chemistry and Medicine (D.S.A., D.F.M.), McArdle Laboratory for Cancer Research (J.Z.), Pediatrics (C.M.S.), and Ophthalmology and Visual Sciences (N.S.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (Z.L.).
Christine M
CM
Sorenson
From the Departments of Surgery (Z.L., S.M., J.R., Q.W., B.L.), Pathology and Laboratory Medicine (B.L.), Biomolecular Chemistry and Medicine (D.S.A., D.F.M.), McArdle Laboratory for Cancer Research (J.Z.), Pediatrics (C.M.S.), and Ophthalmology and Visual Sciences (N.S.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (Z.L.).
Nader
N
Sheibani
From the Departments of Surgery (Z.L., S.M., J.R., Q.W., B.L.), Pathology and Laboratory Medicine (B.L.), Biomolecular Chemistry and Medicine (D.S.A., D.F.M.), McArdle Laboratory for Cancer Research (J.Z.), Pediatrics (C.M.S.), and Ophthalmology and Visual Sciences (N.S.), University of Wisconsin School of Medicine and Public Health, Madison; and Department of Vascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (Z.L.). liub@surgery.wisc.edu.
Bo
B
Liu
D019264:Adoptive Transfer; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency; D016026:Bone Marrow Transplantation; D002130:Calcium Phosphates / Q000633:toxicity; D002460:Cell Line; D002465:Cell Movement; D004195:Disease Models, Animal; D007249:Inflammation; D008264:Macrophages / Q000502:physiology* / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology / Q000637:transplantation; D010196:Pancreatic Elastase / Q000633:toxicity; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000627:therapeutic use; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use; D015854:Up-Regulation
D001057:Apolipoproteins E; D002130:Calcium Phosphates; D011994:Recombinant Proteins; D019700:Thrombospondin 1; D000804:Angiotensin II; C020243:calcium phosphate; D010196:Pancreatic Elastase
abdominal aortic aneurysm; inflammation; monocytes