Mode of Endometrial Angiogenesis

Although it is clear that complete revascularization of the endometrium takes place each cycle, the exact process involved is far from clear. Histological studies to date have fallen short of clearly capturing the nature of the growth or its timing relative to the changes in the other components of the endometrium during the menstrual cycle. The regeneration of the human endometrium is a unique process, and there is little with which to compare it; menstruation occurs only in humans, some Old World primates, and a couple of other rare species, so research animal models of endometrial regeneration are quite limited (recently, Brasted et al. [5] reported on a mouse model of menstruation, based on

Figure 4 A thick frozen section of the endometrium from a rhesus monkey at the mid-proliferative stage of the cycle immunostained with an antibody to the type 2 VEGF receptor (KDR), which is expressed almost exclusively on endothelial cells. Note the richness of small vessels in the endometrium (upper portion of image) versus the myometrium (lower quarter of the image), especially around the endometrial glands. A paraglandular capillary plexus is clearly discernible around the gland in the lower right quadrant of the endometrium (from Ref. [4]. Copyright 2000, The Endocrine Society).

Figure 4 A thick frozen section of the endometrium from a rhesus monkey at the mid-proliferative stage of the cycle immunostained with an antibody to the type 2 VEGF receptor (KDR), which is expressed almost exclusively on endothelial cells. Note the richness of small vessels in the endometrium (upper portion of image) versus the myometrium (lower quarter of the image), especially around the endometrial glands. A paraglandular capillary plexus is clearly discernible around the gland in the lower right quadrant of the endometrium (from Ref. [4]. Copyright 2000, The Endocrine Society).

progesterone treatment and rapid withdrawal, that may in part address this gap). The most extensive studies of endometrial angiogenesis have been carried out by Rogers and co-workers [6], who have concluded, somewhat surprisingly, that it does not involve the sort of progressive sprouting from existing microvessels that characterizes the angiogenesis associated with tumor growth, wound healing, and vascularization of the corpus luteum after ovulation. This is based mainly on their failure to observe sprouts or markers for sprouting endothelial cells in the endometrium, and their observation that proliferation of endothelial cells occurs primarily within the walls of existing vessels. Instead they find an elevation in average vessel segment length in the mid- to late-proliferative endometrium and an increase in the number of vessel junctions in the early to mid-secretory phase. For these reasons they suggest that the linear growth of endometrial vessels is due mainly to vessel elongation brought about by the proliferation of endothelial cells in response to mechanical (stretch) or chemical signals from the surrounding, growing endometrial tissue. At the level of the subepithelial microvasculature, they propose that new channels may arise by a process called intussusception, which, simply put, involves one vessel splitting lengthwise to give rise to two vessels. Although these processes probably are involved in the elongation of endometrial vessels, especially in menstruating species in which the endometrium becomes progressively thicker, and the remodeling of capillary beds within the endometrium, further work is needed to determine whether or not angio-genesis via endothelial cell sprouting also occurs. The subepithelial capillary plexus, after all, is completely lost with menstruation. Furthermore, injection or corrosion cast preparations of the endometrial vasculature of experimental animals, which do undergo substantial remodeling during the reproductive cycle [3], often show the presence of blind-ended capillary branches during the portion of the cycle when estrogen is rising. These are generally interpreted to be new capillary sprouts. If sprouting occurs in the endometrium of animals in which the endometrium is not lost, it seems likely that it would also occur when an entirely new vasculature is regenerated. Better methods to visualize endometrial vessels, down to the level of capillaries, in intact, high-quality endometrial samples collected at all stages of the cycle from experimental primates will be required to resolve this issue.

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Essentials of Human Physiology

Essentials of Human Physiology

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