Background: Angiogenesis is a major promotor of tumor progression and metastasis. Nevertheless, it is undetermined how angiogenesis-related genes (ARGs) influence bladder cancer.

Methods: The profiles of bladder cancer gene expression were collected from the TCGA-BLCA cohort. The LASSO regression analysis was used to build an angiogenesis-related signature (ARG_score) with the prognostic ARGs. Verification analyses were conducted across the GSE48075 dataset to demonstrate the robustness of the signature. Differences between the two risk groups based on clinical outcomes, immune landscape, mutation status, chemotherapeutic effectiveness for anticancer drugs, and immunotherapy efficacy were analyzed. A nomogram was developed to improve the clinical efficacy of this predictive tool. The expression levels of model genes in normal bladder epithelial cell lines (SV-HUC-1) and bladder cancer cell lines (T24 and 5637) were detected by qRT-PCR assay.

Results: Four angiogenesis-associated gene signature was constructed based on the LASSO regression algorithm. The signature showed independent risk factors of overall survival for bladder cancer, validated using two external survival datasets. Additionally, we built a prognostic nomogram to improve the practicality of the ARG_score. High-risk individuals showed stronger immunocyte infiltration, immune-related functions, elevated expression of immune checkpoints, reduced TIDE score, and higher combined IPS-PD-1 and IPS-CTLA4 scores, suggesting a heightened responsiveness to immune checkpoint inhibitors. Furthermore, patients with low and high risk showed distinct responsiveness to anticancer drugs. The expression levels of 5 model genes (COL5A2, JAG1, MSX1, OLR1, and STC) were significantly increased in bladder cancer cell lines (T24 and 5637) compared with the normal bladder epithelial cell line SV-HUC-1.

Conclusions: The model constructed based on ARGs may have wide application in predicting outcomes and therapeutic responses.