FIG. 9.

The proposed role of VEGFA in endometrial epithelial cell proliferation and stromal remodeling. As E₂ levels rise during proestrus (or in response to exogenous E₂ in immature or ovariectomized animals), Vegfa is expressed by LE cells (Phase 1). VEGFA induces a large increase in the permeability of stromal microvessels, flooding the stroma with plasma, the edema that is the sine qua non of the early effects of E₂ on the uterus (Phase 2). The plasma is rich in growth factors such as IGF1 and carries additional E₂ bound to serum proteins. Growth factors and E₂ act in concert to induce maximal LE cell proliferation (Phase 3). The plasma also contains plasminogen that triggers the collagenolytic cascade and the degradation of the stromal extracellular matrix (ECM), as well as fibrinogen, which is converted to fibrin, creating a temporary matrix that promotes cell proliferation, cell migration, and angiogenesis [8]. The E₂ also primes stromal fibroblasts for later proliferation in response to progesterone.