Angiogenic Regulation in Ovarian Follicle Development

Ovarian follicle development relies on precisely orchestrated vascular growth to supply oxygen, nutrients and endocrine signals to the maturing oocyte and its surrounding somatic cells. In early stages, a nascent capillary network forms around the follicle’s theca layer under the influence of pro-angiogenic mediators such as vascular endothelial growth factor A (VEGF-A) and angiopoietins. As follicles progress from primordial through antral stages, hypoxic microenvironments trigger hypoxia-inducible factor 1α (HIF-1α) to upregulate VEGF-A and enhance vessel permeability. Follicle-stimulating hormone (FSH) and luteinising hormone (LH) signalling further modulate the balance of pro- and anti-angiogenic isoforms to fine-tune vascular remodelling. During the periovulatory LH surge, dynamic changes in transcription factors, chromatin structure and paracrine feedback coordinate endothelial cell proliferation and lumen formation to ensure rapid perfusion of the preovulatory follicle. Following ovulation, luteinization of residual granulosa cells is accompanied by intensive angiogenesis to establish the corpus luteum. Dysregulation of angiogenic pathways may underlie ovarian pathologies such as poor follicle vascularisation, subfertility and ovarian hyperstimulation syndrome. Understanding the cellular and molecular drivers of angiogenesis in folliculogenesis offers avenues for improving assisted reproduction and fertility preservation.

Research from Nature Portfolio

Studies have shown that exposure of frozen-thawed human ovarian cortical tissue to elevated FSH concentrations markedly alters VEGF-A expression in developing follicles. Whereas physiological FSH levels maintained VEGF-A secretion, supra-physiological concentrations caused a significant decline in VEGF-A production by growing follicles, suggesting that hormonal milieu at reimplantation can critically affect graft vascularisation. In rat models, luteinising hormone surge–induced chromatin remodelling permits CCAAT/enhancer-binding protein β (C/EBPβ) to bind the Vegf promoter in granulosa cells. Concurrent reductions in repressive histone marks facilitate transcriptional activation of Vegf, driving the angiogenic switch during luteinization. These findings highlight how gonadotrophin-mediated signalling and epigenetic mechanisms converge on VEGF regulation to orchestrate follicular vascular maturation.

Angiogenic Regulation in Ovarian Follicle Development publication trend

The graph below shows the total number of articles in angiogenic regulation in ovarian follicle development across all publications each year (not limited to Nature Index journals).

Technical terms

Angiogenesis: Formation of new blood vessels from pre-existing vasculature, essential for follicle growth and corpus luteum formation.

Folliculogenesis: Sequential development of ovarian follicles from primordial to preovulatory stages.

Granulosa cells: Somatic cells lining the follicle that support oocyte maturation, steroidogenesis and angiogenic signalling.

Vascular endothelial growth factor A (VEGF-A): Principal pro-angiogenic cytokine driving endothelial proliferation and vessel permeability.

Hypoxia-inducible factor 1α (HIF-1α): Transcription factor stabilised under low oxygen that upregulates genes involved in angiogenesis and metabolism.

Luteinization: Process by which post-ovulatory granulosa cells transform into progesterone-secreting luteal cells, accompanied by intensive angiogenesis.

References

1. High FSH levels impair VEGF secretion of human, frozen-thawed ovarian cortical tissue in vitro. Scientific Reports (2024).
2. C/EBPβ regulates Vegf gene expression in granulosa cells undergoing luteinization during ovulation in female rats. Scientific Reports (2019).
3. Identification of potential angiogenic biomarkers in human follicular fluid for predicting oocyte maturity. Frontiers in Endocrinology (2023).
4. Regulation of the ovarian follicular vasculature. Reproductive Biology and Endocrinology (2006).
5. The balance of proangiogenic and antiangiogenic VEGFA isoforms regulate follicle development. Cell and Tissue Research (2012).