Cdh5, also known as VE-cadherin, is a cadherin expressed by endothelial cells. It is crucial for vascular morphogenesis, maintaining vascular integrity and lymphatic function. It is involved in cell adhesion within endothelial and vascular cells, and is associated with pathways like cGAS-STING in endothelial cells, which is relevant to doxorubicin-induced cardiotoxicity [2].

In a study on lymphedema, six different variants (five missense and one nonsense) of the CDH5 gene were detected in 235 Italian patients with lymphedema who had negative results for known lymphedema genes. This indicates that CDH5 variants may contribute to the onset of lymphedema, although further in vitro studies are needed [1]. In the context of doxorubicin-induced cardiotoxicity, endothelial cell-specific conditional Sting deficiency (Stingflox/flox/Cdh5-CreERT) mice were used. The results showed that the cGAS-STING pathway in cardiac endothelial cells is activated by doxorubicin, leading to a series of events including reduced NAD levels and mitochondrial dysfunction. Pharmacological inhibition of related kinases effectively ameliorated cardiotoxicity, suggesting the cGAS-STING pathway in endothelial cells as a potential therapeutic target [2].

In summary, Cdh5 plays essential roles in vascular-related biological functions. Studies using gene-modified mouse models, such as the Stingflox/flox/Cdh5-CreERT mice, have revealed its significance in disease conditions like doxorubicin-induced cardiotoxicity. The potential association of Cdh5 variants with lymphedema also indicates its importance in understanding the genetic basis of this disease. These findings contribute to a better understanding of the functions of Cdh5 and may provide new directions for related disease treatments.

References:

1. Michelini, Sandro, Ricci, Maurizio, Amato, Bruno, Dautaj, Astrit, Bertelli, Matteo. 2021. CDH5, a Possible New Candidate Gene for Genetic Testing of Lymphedema. In Lymphatic research and biology, 20, 496-506. doi:10.1089/lrb.2020.0089. https://pubmed.ncbi.nlm.nih.gov/34882481/

2. Luo, Wei, Zou, Xiaoyi, Wang, Yidan, Sun, Aijun, Ge, Junbo. 2023. Critical Role of the cGAS-STING Pathway in Doxorubicin-Induced Cardiotoxicity. In Circulation research, 132, e223-e242. doi:10.1161/CIRCRESAHA.122.321587. https://pubmed.ncbi.nlm.nih.gov/37154056/