Matricellular Protein SPARCL1 Regulates Blood Vessel Integrity and Antagonizes Inflammatory Bowel Disease

Abstract

Background The understanding of vascular plasticity is key to defining the role of blood vessels in physiologic and pathogenic processes. In the present study, the impact of the vascular quiescence marker SPARCL1 on angiogenesis, capillary morphogenesis, and vessel integrity was evaluated. Methods Angiogenesis was studied using the metatarsal test, an ex vivo model of sprouting angiogenesis. In addition, acute and chronic dextran sodium sulfate colitis models with SPARCL1 knockout mice were applied. Results This approach indicated that SPARCL1 inhibits angiogenesis and supports vessel morphogenesis and integrity. Evidence was provided that SPARCL1-mediated stabilization of vessel integrity counteracts vessel permeability and inflammation in acute and chronic dextran sodium sulfate colitis models. Structure-function analyses of purified SPARCL1 identified the acidic domain of the protein necessary for its anti-angiogenic activity. Conclusions Our findings inaugurate SPARCL1 as a blood vessel–derived anti-angiogenic molecule required for vessel morphogenesis and integrity. SPARCL1 opens new perspectives as a vascular marker of susceptibility to colitis and as a therapeutic molecule to support blood vessel stability in this disease.

Angiocrine Regulation of Epithelial Barrier Integrity in Inflammatory Bowel Disease

“…Exaggerated inflammation in Sc1 KO animals was further supported by an increased detection of fibrosis and the presence of tertiary lymphoid structures similar to the human chronic disease. Altogether, these results indicated that intestinal angiocrine functions may establish a chemical barrier affecting both, epithelial and endothelial cell barrier functions in IBD ( 122 ).…”

“…Specific support for angiocrine functions in IBD was obtained from a recent report on an increased susceptibility for acute and chronic DSS-induced colonic inflammation in mice lacking the angiocrinely active SPARCL1 protein ( 122 ). SPARCL1 is almost exclusively expressed in vascular cells in the colon ( 119 , 123 , 124 ).…”

“…In this framework, the six genes identified in endothelial cells from colorectal carcinoma may exhibit the highest relevance for IBD (see Table 1 ). Interestingly, SPARCL1, which has been shown to affect susceptibility to experimental colitis in mice was part of this group ( 122 ). In summary, this analysis identified several interesting candidates, which may participate in the angiocrine inter-barrier communication in IBD.…”

Contribution of Blood Vessel Activation, Remodeling and Barrier Function to Inflammatory Bowel Diseases

“…PDGF-B/PDGFR-β knockout models in mice showed reduced mural cell coverage and increased vessel permeability [ 159 , 161 , 162 ]. In the DSS colitis model, vessel coverage has been found to promote the stabilization of the vascular barrier, decreasing vessel permeability and inflammation [ 163 , 164 ]. Endothelial IFN-γ receptor knockout leads to increased vessel coverage during DSS-induced colitis in mice [ 33 , 34 ].…”

Rapid qPCR-based quantitative immune cell phenotyping in mouse tissues

“…IHC/qPCR correlation. C57BL/6 mice (n = 12) were treated with 2.5% dextran sulfate sodium (MP Biomedicals, #160110) in the drinking water for 1 week, 16 and mice were sacrificed on day 9 or 10. The spleen, thymus, mesenteric lymph nodes (mLN), and colon were harvested from each animal.…”