Loss of tenascin X gene function impairs injury‐induced stromal angiogenesis in mouse corneas

Abstract

To determine the contribution by tenascin X (Tnx) gene expression to corneal stromal angiogenesis, the effects were determined of its loss on this response in TNX knockout (KO) mice. In parallel, the effects of such a loss were evaluated on vascular endothelial growth factor (VEGF) and transforming growth factor b1 (TGFb1) gene and protein expression in fibroblasts and macrophages in cell culture. Histological, immunohistochemical and quantitative RT-PCR changes determined if Tnx gene ablation on angiogenic gene expression, inflammatory cell infiltration and neovascularization induced by central corneal stromal cauterization. The role was determined of Tnx function in controlling VEGF-A or TGFb1 gene expression by comparing their expression levels in ocular fibroblasts and macrophages obtained from wild-type (WT) and bodywide Tnx KO mice. Tnx was up-regulated in cauterized cornea. In Tnx KO, macrophage invasion was attenuated, VEGF-A and its cognate receptor mRNA expression along with neovascularization were lessened in Tnx KOs relative to the changes occurring in their WT counterpart. Loss of Tnx instead up-regulated in vivo mRNA expression of anti-angiogenic VEGF-B but not VEGF-A. On the other hand, TGFb1 mRNA expression declined in Tnx KO cultured ocular fibroblasts. Loss of Tnx gene expression caused VEGF-A expression to decline in macrophages. Tnx gene expression contributes to promoting TGFb1 mRNA expression in ocular fibroblasts and VEGF-A in macrophages, macrophage invasion, up-regulation of VEGF-A expression and neovascularization in an injured corneal stroma. On the other hand, it suppresses anti-angiogenic VEGF-B mRNA expression in vivo.

Impairment of corneal epithelial wound healing is association with increased neutrophil infiltration and reactive oxygen species activation in tenascin X-deficient mice

“…Immunostaining detected TNX expression in the peripheral stroma, but not in the central, cornea of an uninjured animal as previously reported (data not shown) [ 36 ]. However, during the epithelial healing process TNX protein expression was evident up to 36 h (Fig.…”

High-Throughput Sequencing to Detect Novel Likely Gene-Disrupting Variants in Pathogenesis of Sporadic Brain Arteriovenous Malformations

“…TNXB contributes to angiogenesis and the decrease of TGFb1 expression level in TNXB knockout mice was reported as modulated by VEGF-A. TNXB acts by encouraging neovascularization and by suppressing anti-angiogenic VEGF-B mRNA expression in vivo (Sumioka et al, 2018). Moreover, it is mutated in a small cohort of patients affected by Ehlers-Danlos syndromes, a heterogeneous group of rare monogenic conditions characterized by vascular and generalized connective tissue fragility (Malfait, 2018).…”

Animal Models of Ehlers–Danlos Syndromes: Phenotype, Pathogenesis, and Translational Potential

“…Additional studies in Tnxb –/– mice revealed the presence of reduced femoral bone mass with enhanced osteoclast differentiation and bone-resorbing ability ( Kajitani et al, 2019 ), very mild genito-urinary complications (rectal prolapse in <1%) in female mice compared to uterine and vaginal prolapse seen in clEDS patients ( Egging et al, 2008 ), attenuated stromal neovascularization following cauterization ( Sumioka et al, 2018 ) and gastric dysfunction associated with abnormal gastric sensory function ( Aktar et al, 2019 ). Additionally, Tnxb –/– mice showed increased anxiety-like behavior as well as superior sensorimotor coordination and emotional learning and memory, without differences in locomotor or home cage activity ( Kawakami and Matsumoto, 2011 ; Voermans et al, 2011 ).…”