Proangiogenic Properties of Thrombospondin-4

Abstract

Objective Thrombospondin-4 (TSP-4) is 1 of the 5 members of the thrombospondin protein family. TSP-1 and TSP-2 are potent antiangiogenic proteins. However, angiogenic properties of the 3 other TSPs, which do not contain the domains associated with the antiangiogeneic activity of TSP-1 and TSP-2, have not been explored. In our previous studies, we found that TSP-4 is expressed in the vascular matrix of blood vessels of various sizes and is especially abundant in capillaries. We sought to identify the function of TSP-4 in the regulation of angiogenesis. Approach and Results The effect of TSP-4 in in vivo angiogenesis models and its effect on angiogenesis-related properties in cultured cells were assessed using Thbs4−/−; mice, endothelial cells (EC) derived from these mice, and recombinant TSP-4. Angiogenesis was decreased in Thbs4−/−; mice compared with wild-type mice. TSP-4 was detected in the lumen of the growing blood vessels. Mice expressing the P387 TSP-4 variant, which was previously associated with coronary artery disease and found to be more active in its cellular interactions, displayed greater angiogenesis compared with A387 form. Lung EC from Thbs4−/−; mice exhibited decreased adhesion, migration, and proliferation capacities compared with EC from wild-type mice. Recombinant TSP-4 promoted proliferation and the migration of EC. Integrin and gabapentin α2 receptor α2δ-1 were identified as receptors involved in regulation of EC adhesion, migration, and proliferation by TSP-4. Conclusion TSP-4, an extracellular matrix protein previously associated with tissue remodeling, is now demonstrated to possess proangiogenic activity.

Microglial cell‐derived interleukin‐6 influences behavior and inflammatory response in the brain following traumatic brain injury

“…Among the 630 DE genes at 1 dpl, only four genes ( Neurotensin [Nts], Thrombospondin 4 [Thbs4], Proprotein convertase 1 [Pcsk1] , and Cerebellin 4 Precursor [Cbln4] ) were not significantly affected by the cryolesion per se, but rather by genotype and/or by the interaction between genotype and cryolesion, since their expression showed a trend to be upregulated by the cryolesion and this was blunted by microglial Il6 deficiency (Figure b‐i). Thbs4 is one of the extracellular matrix proteins that promotes vasculature remodeling after cortical lesion (Andersson et al, ; Muppala et al, ), and Nts is an important neuropeptide in the CNS that could be released locally to modulate the wound healing response (St.‐Gelais, Jomphe, & Trudeau, ), suggesting that Il6 ΔMic mice could have a delay in healing, as previously observed in systemic IL‐6 KO mice (Fee et al, ; Swartz et al, ). Pcsk1 is a critical enzyme in the processing of several neurohormones.…”

Effect of Thrombospondin-4 on Pro-inflammatory Phenotype Differentiation and Apoptosis in Macrophages

“…High levels of TSP4 have been detected in remodeling and failing hearts [3][4][5][6][7], several cancers [8][9][10][11][12][13], and atherosclerotic lesions [14]. Recently, new functions have been ascribed to TSP4 in cardiovascular system [5][6][7][14][15][16][17][18][19][20][21][22][23][24][25], cancer [8][9][10][11][12][24][25][26][27][28][29], and nervous system [30][31][32][33][34], but effects of TSP4 on cellular responses and the regulation of TSP4 expression remain poorly understood. For example, with an exception of TGF-beta [25], stimuli inducing TSP4 expression in tissues remain unknown.…”

“…For example, with an exception of TGF-beta [25], stimuli inducing TSP4 expression in tissues remain unknown. Although several cell surface receptors were shown to mediate TSP4 effects [14,24,30,35], signaling and regulation of intracellular processes by TSP4 have received only limited attention.…”

“…Tissue remodeling, inflammation, and angiogenesis often occur simultaneously and are regulated by the same stimuli. We recently reported that TSP4 promotes angiogenesis [24,25] and vascular inflammation in a mouse atherosclerosis model [14]. These observations suggested that TSP4 may play an important role in regulation of inflammation and inflammatory cell responses.…”

Thrombospondins in the transition from myocardial infarction to heart failure

“…Angiogenesis is decreased in TSP-4 −/− mice compared with wild-type mice [78]. In this study TSP-4 was detected in the lumen of the growing blood vessels.…”