Thrombospondin-1 (TSP1) Contributes to the Development of Vascular Inflammation by Regulating Monocytic Cell Motility in Mouse Models of Abdominal Aortic Aneurysm

Abstract

Rationale Histological examination of abdominal aortic aneurysm (AAA) tissues demonstrates extracellular matrix (ECM) 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 (TSP1) 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 TSP1 correlate with vascular disease conditions. Objective To use TSP1 deficient (Thbs1−/−) mice to test the hypothesis that TSP1 contributes to pathogenesis of AAAs. Methods and Results Mouse experimental AAA was induced either through perivascular treatment with calcium phosphate, intraluminal perfusion with porcine elastase, or systemic administration of Angiotensin II. Induction of AAA increased TSP1 expression in aortas of C57BL/6 or apoE−/− mice. Compared to 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 to wildtype counterparts. Adoptive transfer of Thbs1+/+ monocytic cells or bone marrow reconstitution rescued aneurysm development in Thbs1−/− mice. Conclusions TSP1 expression plays a significant role in regulation of migration and adhesion of mononuclear cells, contributing to vascular inflammation during AAA development.

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

“…Further investigations using mice doubly deficient in both ApoE and IL-10 (64) may offer an opportunity to interrogate more closely this relationship. Although our evidence supports an important role for the proposed pathway, we recognize that it is likely that other targets for NO also play a role, such as the repression of thrombospondin-1 (65).…”

Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression

“…However, its underlying molecular and cellular mechanisms remain incompletely understood. Experimental evidence published by several investigative groups, including our own, suggests active interplays between infiltrating macrophages and resident SMCs (Curci and Thompson, 2004;Liu et al, 2015). Vascular SMCs are a major source of extracellular matrix proteins that render elastic property and tensile strength to the aortic wall.…”

“…Male C57BL/6J mice, aged 8-12 weeks, underwent AAA induction by elastase perfusion, as described previously (Pyo et al, 2000;Liu et al, 2015;Wang et al, 2015). In brief, after anesthesia, the abdominal aorta was isolated, and the external diameter of the largest portion of the abdominal aorta was measured with a digital caliber.…”

TIPE2 is negatively correlated with tissue factor and thrombospondin-1 expression in patients with bronchial asthma

“…However, TSP-1 is a multifunctional protein and serves a significant role in inflammation. It has been demonstrated that TSP-1 contributes to the development of vascular inflammation by regulating the cell motility of monocytes in a mouse model of abdominal aortic aneurysm (23). Furthermore, TSP-1 efficiently down-regulates TF-induced coagulation by binding to TFPI and locating to surfaces within the extravascular space following vascular injury (32).…”

“…As a type of tumor necrosis factor-α-induced protein-8, TIPE2 is primarily expressed by the myeloid and lymphoid immune cells, particularly by T lymphocytes, mononuclear cells and macrophages (17,18). TIPE2 is a negative regulator of inflammation in certain diseases including chronic hepatitis B (19), chronic hepatitis C (20), systemic lupus erythematosus (SLE) (21), diabetic nephropathy (22) and abdominal aortic aneurysm (23), suggesting that it serves an important role in the pathogenesis of inflammatory diseases.…”