Cyclic Changes in Endometrial Microvascular Permeability

In addition to being dynamic in terms of growth and regression, the uterine microvasculature may also be one of the most variable in terms of changes in permeability in the body. These changes, which play a critical role in endometrial function, are also governed by VEGF [7, 10], which is the most potent inducer of vascular permeability known.

The first visible effect of estrogens on the rodent uterus is the rapid induction of massive stromal edema [11]. This is readily observable within a few hours as a large increase in uterine size and wet weight. These changes closely resemble those that occur in response to endogenous estrogen during proestrus in the normal adult rat. Although not as outwardly apparent as in rodents, cyclic endometrial edema also takes place in humans during both the midproliferative and mid-secretory phases of the menstrual cycle [12], periods that correspond to increases in estrogen production by first the developing follicle and then the corpus luteum. Furthermore, the administration of exogenous estrogens induces stromal edema in the human endometrium, just as it does in the rat. There have been few studies of uterine edema in other species, but it is likely that it is a universal response to estrogen in mammals.

The estrogen-induced increase in permeability is preceded by a large increase in VEGF expression [7]. Its morphological basis is the formation of gaps between and fenestrae within capillary endothelial cells. VEGF can induce both gaps and fenestrations and is the only factor known to induce the latter effect [13]. Furthermore, administration of an antibody to VEGF prevents estrogen-induced uterine edema [10], conclusive evidence that VEGF is the key factor involved. Estrogen also induces a marked increase in blood flow to the uterus, probably via the induction of increased synthesis of nitric oxide, a potent vasodilator. The combination of an increase in vessel porosity (a route for fluid flow out of the blood vessel) and an increase in blood flow (which creates the pressure that drives the filtration) leads to the translocation of large amounts of fluid from the intravascular to the extravascular space, directly bathing cells of the endometrial stroma in serum.

It is now clear that this increase in permeability is far more than just an interesting biological phenomenon. Increased microvascular permeability plays a fundamental role in both normal and pathological tissue remodeling (reviewed in Ref. [14]). The infusion of the extravascular compartment of a tissue with plasma proteins, such as plas-minogen and fibrinogen, leads to the breakdown of the existent extracellular matrix and formation of a provisional one upon which stromal cells, including endothelial cells, can migrate, proliferate, differentiate, and reorganize. Extra-vascular fibrin deposition occurs in the human endometr-ium during the period of maximum edema, as does a breakdown of its collagenous extracellular matrix. Increased permeability also facilitates the delivery to cells of other essential bloodborne elements, such as oxygen, essential nutrients, serum growth factors, leukocytes and platelets— with their own rich stores of growth modulators—and estrogen-carrying proteins. In the uterus, such enhanced passage of estrogen to target cells may accelerate and sustain the full range of estrogen responses.

Thus, increased permeability is probably an essential requirement for the rapid growth and differentiation of the endometrium. Consistent with this, inhibition of uterine edema with anti-inflammatory steroids significantly retards subsequent uterine epithelial cell proliferation. Furthermore, the induction of transient edema in one horn of rat uteri by ligation of the associated uterine veins (thereby increasing resistance, capillary hydrostatic pressure, and filtration) resulted in the short term in edema, which was followed within days by marked endometrial and myometrial hyper-plasia [15]. The authors concluded that this cell proliferation was triggered by the experimentally-induced edema. In addition to creating the optimal environment for growth, the uterine distension caused by edema may trigger stretch-activated pathways that further stimulate the proliferation of cells.

In rodents, the interstitial fluid subsequently enters and distends the uterine lumen during estrus, which is when mating occurs. This may create the optimal environment for sperm transport and capacitation.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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