Vascular biology of uterine fibroids: connecting fibroids and vascular disorders

Abstract

Fibroids are benign tumors caused by the proliferation of myometrial smooth muscle cells in the uterus that can lead to symptoms such as abdominal pain, constipation, urinary retention, and infertility. While traditionally thought of as a disease process intrinsic to the uterus, accumulating evidence suggests that fibroid growth may be linked with the systemic vasculature system, although cell-intrinsic factors are certainly of principal importance in their inception. Fibroids are associated with essential hypertension and preeclampsia, as well as atherosclerosis, for reasons that are becoming increasingly elucidated. Factors such as the renin-angiotensin-aldosterone system, estrogen, and endothelial dysfunction all likely play a role in fibroid pathogenesis. In this review, we lay out a framework for reconceptualizing fibroids as a systemic vascular disorder, and discuss how pharmaceutical agents and other interventions targeting the vasculature may aid in the novel treatment of fibroids.

Figure 1.. Schematic presentation of the association of uterine fibroids with systemic vascular disorders.

1. Similar to preeclampsia, the association of uterine fibroids with hypertension may be mediated by ET-1. 2. RAA system activation and hypertension-mediated smooth muscle injury and ECM upregulation may explain the association between uterine fibroids and hypertension. 3. Uterine fibroids and atherosclerosis are resemblant in terms of pathological features and associated risk factors. Angiotensin (Ang); Endothelin-1 (ET-1); Extracellular matrix (ECM); Renin-angiotensin-aldosterone (RAA); Transforming growth factor β (TGF-β).

Figure 2.. Schematic presentation of vascular dysfunction and vasoactive mediators involved in uterine fibroid pathogenesis.

1. Aberrant activation of the RAA system is implicated in fibroid cell proliferation through the actions of Ang-II and aldosterone. 2. The tumorigenic actions of Ang-II are potentiated via ACE and ATR gene polymorphisms whereas those of aldosterone may be mediated by MAPKs and ERKs. 3. Estrogen can augment the actions of the RAA system in fibroids by upregulating hepatic angiotensinogen production and AT₂R expression in the uterine vasculature. 4. Ang-II may additionally upregulate TGF-β expression and ECM synthesis. 5. Vascular dysfunction in uterine fibroids may create a local hypoxic milieu that upregulates HIF-1α, and in turn, ET-1 expression. In the fibroid cell, ET-1 activates the enzyme SphK1, promoting the conversion of sphingosine to S1P, which inhibits apoptotic cascades and enhances cell survival. 6. Increased basal NO induces ROS production, inhibition of apoptosis, endothelial dysfunction, and systemic vascular disorders. 7. Collectively, increased cellular proliferation, decreased apoptosis and enhanced ECM synthesis promote fibroid growth. Dashed lines denote hypothesized mechanisms. Angiotensin (Ang); Angiotensin converting enzyme (ACE); Angiotensin receptor (ATR); Endothelin-1 (ET-1); Extracellular matrix (ECM); Extracellular regulated kinases (ERKs); Gonadotrophin releasing hormone (GnRH); Hypoxia inducible factor 1α (HIF-1α); Mineralocorticoid receptor (MR); Mitogen activated protein kinases (MAPKs); Nitric oxide (NO); Reactive oxygen species (ROS); Renin angiotensin aldosterone (RAA); Sphingosine kinase 1 (SphK1); Sphingosine-1-phosphate (S1P); Transforming growth factor β (TGF-β).