The impact of heterozygous BRCA1 mutations on ovarian angiogenesis

BRCA1/2 mutations are classically associated with hereditary breast and ovarian cancer, yet growing evidence indicates that even heterozygous BRCA1 status may alter ovarian physiology before malignant transformation. Carriers of BRCA1 mutations display reduced ovarian reserve and accelerated reproductive ageing, but the cellular and molecular mechanisms behind these changes remain unclear. Given the fundamental role of angiogenesis in follicle survival and stromal homeostasis, we investigated whether BRCA1 haploinsufficiency disrupts the ovarian microvascular environment, predisposing to both impaired ovarian function and a pro-tumorigenic niche. We isolated ovarian endothelial cells (OVECs) from biopsies of healthy women, carrying and non-carrying the BRCA1 mutation. Our observations indicated distinct growth behaviours in vitro , particularly in terms of morphology and replication rate. Transcriptomic analysis revealed a distinct gene expression profile in mut compared to WT OVECs. Mut cells exhibited an enrichment of gene signatures associated with vascular remodelling, such as migration, proliferation, and sensitivity to endothelial-to-mesenchymal transition. Functionally, mut OVECs showed increased angiogenic behaviour and a shift toward mesenchymal traits. Histological analysis of ovarian tissues confirmed aberrant vascular architecture and increased microvessel density in BRCA1-mut ovaries, consistent with endothelial activation and remodelling. In conclusion, phenotypic and functional differences between wild-type and mut OVECs were proved, demonstrating that heterozygous mutations in BRCA1 can induce a tissue-specific endothelial dysfunction.