Vascular tenascin‐C regulates cardiac endothelial phenotype and neovascularization

Abstract

Microenvironmental cues mediate postnatal neovascularization via modulation of endothelial cell and bone marrow-derived endothelial progenitor cell (EPC) activity. Numerous signals regulate the activity of both of these cell types in response to vascular injury, which suggests that parallel mechanisms regulate angiogenesis in the vascular beds of both the heart and bone marrow. To identify mediators of such shared pathways, in vivo bone marrow/cardiac phage display biopanning was performed and led to the identification of tenascin-C as a candidate protein. Functionally, tenascin-C inhibits cardiac endothelial cell spreading and enhances migration in response to angiogenic growth factors. Analysis of human coronary thrombi revealed tenascin-C protein expression colocalized with the endothelial cell/EPC marker Tie-2 in intrathrombi vascular channels. Immunostains in the rodent heart demonstrated that tenascin-C also colocalizes with EPCs homing to sites of cardiac angiogenic induction. To determine the importance of tenascin-C in cardiac neovascularization, we used an established cardiac transplantation model and showed that unlike wild-type mice, tenascin-C-/- mice fail to vascularize cardiac allografts. This demonstrates for the first time that tenascin-C is essential for postnatal cardiac angiogenic function. Together, our data highlight the role of tenascin-C as a microenvironmental regulator of cardiac endothelial/EPC activity.

Identification of the novel localization of tenascinX in the monkey choroid plexus and comparison with the mouse

“…The presence of Tn-X+ and Tn-C+ was confirmed in some blood vessels in the parenchyma of the cerebellum and medulla oblongata ( Figure 2C, E). These results were consistent with previous reports of vascular localization of Tn-X and Tn-C (Matsumoto et al, 1994;Hasegawa et al, 1997;Ballard et al, 2006). In addition, a leptomeningeal Tn-X+ trabecular structure was also observed in the cerebellum ( Figure 2C).…”

Impaired cornea wound healing in a tenascin C-deficient mouse model

“…24 Our in vitro experiment revealed that lacking osteopontin inhibited phosphorylation of Smad3 and p38 in cultured ocular fibroblasts that might explain the mechanism of attenuation of TGFb-related fibrogenic reaction in osteopontin-null fibroblasts. 25 As for the mechanism of impairment of TGFb-related healing and fibrogenic gene expression by the loss of tenascin C was reported in experimental lung fibrosis model in mice, [26][27][28][29] this report also showed that lacking tenascin C decreases the level of total Smad3 (not Smad2), 30 but did not inhibit the phosphorylation of Smad3, as examined by western blotting. The authors of this report speculate that reduction of total Smad3 protein might account for the impairment of TGFb/ Smad3 signal and resultant inhibition of fibrogenic behaviors of fibroblasts in lung tissue.…”

Higher Serum Tenascin-C Levels Reflect the Severity of Heart Failure, Left Ventricular Dysfunction and Remodeling in Patients With Dilated Cardiomyopathy

“…28 In addition, endothelial cells and vascular smooth muscle cells of various organs have the potential to synthesize TN-C under these same stimulations. 10,29 The elevated levels of circulating soluble inflammatory mediators in heart failure patients might also stimulate endothelial cells of, for example, the liver, or lung, to secrete TN-C into the blood stream.…”