Relevance of angiogenesis in autoimmune testis inflammation

Abstract

Experimental autoimmune orchitis (EAO) is a useful model to study organ-specific autoimmunity and chronic testicular inflammation. This model reflects testicular pathological changes reported in immunological infertility in men. Progression of EAO in rodents is associated with a significantly increased percentage of testicular endothelial cells and interstitial testicular blood vessels, indicating an ongoing angiogenic process. Vascular endothelial growth factor A (VEGFA), the main regulator of physiological and pathological angiogenesis, can stimulate endothelial cell proliferation, chemotaxis and vascular permeability. The aim of this study was to explore the role of VEGFA in the pathogenesis of testicular inflammation. Our results found VEGFA expression in Leydig cells, endothelial cells and macrophages in testis of rats with autoimmune orchitis. VEGFA level was significantly higher in testicular fluid and serum of rats at the end of the immunization period, preceding testicular damage. VEGF receptor (VEGFR) 1 is expressed mainly in testicular endothelial cells, whereas VEGFR2 was detected in germ cells and vascular smooth muscle cells. Both receptors were expressed in testicular interstitial cells. VEGFR2 increased after the immunization period in the testicular interstitium and VEGFR1 was downregulated in EAO testis. In-vivo-specific VEGFA inhibition by Bevacizumab prevented the increase in blood vessel number and reduced EAO incidence and severity. Our results unveil relevance of VEGFA-VEGFR axis during orchitis development, suggesting that VEGFA might be an early marker of testicular inflammation and Bevacizumab a therapeutic tool for treatment of testicular inflammation associated with subfertility and infertility.

Varicocele and testicular cord torsion: immune testicular microenvironment imbalance

“…HIF-1α regulates the expression of vascular endothelial growth factor (VEGF) that could be involved in many VC and TCT pathophysiological effects. In an experimental model of autoimmune orchitis we demonstrate that involvement of VEGFA-VEGFR is associated with a significantly increased percentage of interstitial testicular blood vessels, suggesting that VEGFA might be an early marker of testicular inflammation ( Gualdoni et al, 2021 ). Chakraborty et al (1985) noted a significant increase in the percentage of total blood vessels in VC patients with severely affected testes compared to controls.…”

A landscape of differentiated biological processes involved in the initiation of sex differentiation in zebrafish

“…Moreover, in the cluster of development-related processes, regulation of cell population proliferation was linked to blood vessel development (Figure 6B). In mammals and human, it was proposed that the cytokines and the ERK1/2 signaling pathway are likely involved in Sertoli cell proliferation (Meroni, Galardo et al 2019), and the progression of chronic testicular inflammation is associated with the proliferation of testicular endothelial cells in rodents (Gualdoni, Jacobo et al 2021). Although little is known about the blood vessel formation in the testis under normal physiological and genetic condition, our data support a hypothesis that the vasculogenesis might begin at the onset of testis differentiation and might be promoted by immune-induced cytokines production.…”

Molecular Mechanism of the Effect of Zhizhu Pill on Gastroesophageal Reflux Disease Based on Network Pharmacology and Molecular Docking

“…Activation of Akt1 is associated with inflammation, oxidative stress, and accumulation of oxidized lipids, and these events form a positive feedback loop that exacerbates the consequences of oxidative stress [ 47 ]. VEGFA can stimulate endothelial cell proliferation, chemotaxis, and vascular permeability, and some studies suggest that the expression of VEGFA is closely related to inflammation and can be used as an early marker of inflammatory diseases [ 48 ]. In summary, targets predicted in this study are all involved in the regulation of oxidative stress and inflammation, and these results corroborate the feasibility of ZZP in the treatment of GERD at the molecular level.…”