Mechanical signaling in reproductive tissues: mechanisms and importance

Abstract

The organs of the female reproductive system are among the most dynamic tissues in the human body, undergoing repeated cycles of growth and involution from puberty through menopause. To achieve such impressive plasticity, reproductive tissues must respond not only to soluble signals (hormones, growth factors, and cytokines) but also to physical cues (mechanical forces and osmotic stress) as well. Here, we review the mechanisms underlying the process of mechanotransduction-how signals are conveyed from the extracellular matrix that surrounds the cells of reproductive tissues to the downstream molecules and signaling pathways that coordinate the cellular adaptive response to external forces. Our objective was to examine how mechanical forces contribute significantly to physiological functions and pathogenesis in reproductive tissues. We highlight how widespread diseases of the reproductive tract, from preterm labor to tumors of the uterus and breast, result from an impairment in mechanical signaling.

Keywords: ROCK/Rho kinase; cervical insufficiency; endometriosis; extracellular matrix; fibroids; mechanotransduction.

Figure 1.

Attenuated signaling in leiomyoma may lead to impaired feedback, excessive ECM deposition, and growth. Mechanical signaling and soluble signaling are shown schematically. Mechanical stress activates integrins, leading to activation of Rho, contraction of myosin, stiffening of the cell, and secretion of ECM. Blockage of mechanical signaling, depicted by double bars, could interrupt the feedback loop, leading to secretion of excessively stiff and abundant ECM and leiomyoma growth. ECM indicates extracellular matrix.

Figure 2.

The cervical ECM during pregnancy and parturition. A, The cervix is composed of 3 zones of structured collagen: the outermost and innermost zones contain fibers arranged longitudinally (parallel to the canal), while the middle zone contains fibrils that are oriented circumferentially. This arrangement is designed to withstand the weight imposed by the gravid uterus. B, The ECM remodeling is essential for cervical dilation during labor and is initiated by the concerted action of soluble mediators and extrinsic forces imposed by the fetal presenting part. The increase in HA (cross-linked to versican) promotes tissue hydration through osmosis and spaces out collagen fibers, thus allowing the cervix to soften while remaining closed. Breakdown of HA and versican by HAse and ADAMTS1 facilitates cervical effacement and dilation during labor. HA indicates hyaluronic acid; HAse, hyaluronidase; ADAMTS 1, a disintegrin and metalloproteinase with thrombospondin-like repeats 1; ECM indicates extracellular matrix.

Figure 3.

The role of mechanical signaling pathways in embryo implantation. Mechanical stress caused by the presence of the embryo, as well as by uterine contractions, leads to the activation of epithelial sodium channels (ENaCs) and downstream production of prostaglandin E2 (PGE2). Soluble LPA molecules signal via LPA3 receptors and downstream Rho/Rho-associated protein kinase (ROCK)/MLP to direct actin organization into stress fibers, promoting stromal cell decidualization. Additionally, LPA signaling also directs prostaglandin production and release. Prostaglandins promote stromal cell decidualization, further uterine contraction, and closure of the uterine lumen, all of which are necessary for successful implantation. LPA indicates lysophosphatidic acid.

Figure 4.

Mechanical signaling processes involved in follicle development and oocyte maturation. A, The luteinizing hormone (LH) surge results in increased transcription of genes involves in proteolysis, inflammation, vascular permeability, and contraction. B, Weakening of follicular wall and of basement membrane (BM) separating granulosa and theca layers. C, Diffusion of endothelin 2 (EDN2) to theca externa layer results in contraction of smooth muscle cell (SMC) and further increases tension in follicle wall. D, Rupture of the follicle and expulsion of the oocyte ensues.

Figure 5.

Mammary cell involution in response to stretch. Mechanical stretch imposed on mammary alveolar cells by milk stasis secondary to weaning activates the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 (ERK1/2) and induces expression of the mechanosensitive transcription factor STAT3. Downstream of these molecules, increased expression of the transcription factor c-fos and its association into AP-1 dimers results in the expression of proapoptosis genes. One such gene is leukemia inhibitory factor (LIF), which feedbacks on the cell to promote further activation of STAT3, thereby perpetuating the apoptotic signaling pathway. Moreover, STAT3 activates 2 regulatory subunits of PI3K (p50-α and p55-α), which in turn inhibits AKT phosphorylation. Phosphorylated AKT provides a critical cell survival signal that must be silenced during mammary cell involution. AKT indicates protein kinase; STAT3, signal transducers and activators of transcription 3.