The mammalian placenta is the organ through which respiratory gases, nutrients, and wastes are exchanged between the maternal and fetal systems. Thus, transplacental exchange provides for all the metabolic demands of fetal growth and development. The rate of transplacental exchange depends primarily on the rates of uterine (maternal placental) and umbilical (fetal placental) blood flows. In fact, increased uterine vascular resistance and reduced uterine blood flow can be used as predictors of high risk pregnancies and are associated with fetal growth retardation. The rates of placental blood flow, in turn, are dependent on placental vascularization, and placental angiogenesis is therefore critical for the successful development of viable, healthy offspring. Recent studies, including gene knockouts in mice, indicate that the vascular endothelial growth factors represent a major class of placental angiogenic factors. Other angiogenic factors, such as the fibroblast growth factors or perhaps the angiopoietins, also may play important roles in placental vascularization. In addition, recent observations suggest that these angiogenic factors interact with the local vasodilator nitric oxide to coordinate placental angiogenesis and blood flow. In the future, regulators of angiogenesis that are currently being developed may provide novel and powerful methods to ensure positive outcomes for most pregnancies.
The rate of fetal growth and subsequent birth weight are major determinants of postnatal survival and growth. Because the placenta is the organ through which respiratory gases, nutrients, and wastes are transported between the maternal and fetal systems, its primary function is to supply the metabolic substrates necessary to support fetal growth. Placental growth and development, therefore, are critical for normal fetal growth and development. During the last half of gestation in mammals, growth of the fetus is exponential, whereas utero-placental growth slows or ceases. Nevertheless, unless placental transport capacity keeps pace with the continually increasing demands of the fetus, fetal growth will be compromised. Studies over the last two decades have shown that placental transport capacity does indeed keep pace with fetal growth. This increase in placental function can be accounted for primarily by continual increases in placental (uterine and umbilical) blood flows, associated with increased placental vascularity. Placental vascular growth and development, in turn, are probably regulated by angiogenic factors produced by the placental tissues themselves. These placental angiogenic factors are produced primarily by the maternal placental tissues, are heparin-binding, and seem to be related to the fibroblast growth factor family. Further elucidation of the factors responsible for placental growth and vascular development is critical for an improved understanding of uteroplacental-fetal interactions, which result in delivery of a healthy offspring.
In adult tissues, capillary growth (angiogenesis) occurs normally during tissue repair, such as in healing of wounds and fractures. Rampant capillary growth is associated with various pathological conditions, including tumor growth, retinopathies, hemangiomas, fibroses and rheumatoid arthritis. The female reproductive organs (i.e., ovary, uterus, and placenta) exhibit dynamic, periodic growth and regression accompanied by equally dramatic changes in rates of blood flow. It is not surprising, therefore, that they are some of the few adult tissues in which angiogenesis occurs as a normal process. Thus, the female reproductive system provides a unique model for studying regulation of angiogenesis during growth and differentiation of normal adult tissues. Ovarian, uterine, and placental tissues recently have been shown to contain and produce angiogenic and anti-angiogenic factors. This review discusses the current state of knowledge regarding angiogenic processes and their regulation in female reproductive tissues. In addition, implications of this research for regulation of fertility as well as for control of angiogenesis in other normal and pathological processes are discussed.
The ovarian corpus luteum plays a critical role in reproduction because it is the primary source of circulating progesterone. After ovulation, as the corpus luteum forms from the wall of the ruptured follicle, it grows and vascularizes extremely rapidly. In fact, the rates of tissue growth and angiogenesis in the corpus luteum rival those of even the fastest growing tumors. Thus, the corpus luteum provides an outstanding model for studying the factors that regulate the angiogenic process, which is critical for normal tissue growth, development, and function. In agreement with data from other tissues, vascular endothelial growth factors (VEGF) seem to be a major angiogenic factor responsible for vascularization of the developing corpus luteum. Recent data suggest that luteal expression of VEGF occurs primarily in specific perivascular cells, including arteriolar smooth muscle and capillary pericytes, and is regulated primarily by oxygen levels. In addition, soon after ovulation, pericytes derived from the thecal compartment appear to be the first vascular cells to invade the developing luteal parenchyma. The granulosa-derived cells produce a factor that stimulates pericyte migration. Moreover, nitric oxide (NO), which is a potent vasodilator and can stimulate VEGF production and angiogenesis, is expressed in endothelial cells of luteal arterioles and capillaries, often in association with expression of VEGF by luteal perivascular cells. Thus, we have proposed a model for the initial process of luteal vascularization in which hypoxia plays a major role. In this model, which we believe will apply to other tissues as well, a paracrine loop exists between the vascular endothelial cells, which produce NO, and the peri-endothelial cells (vascular smooth muscle and pericytes), which produce VEGF, to ensure coordinate regulation of luteal vasodilation and angiogenesis.
The placenta is the organ that transports nutrients, respiratory gases, and wastes between the maternal and fetal systems. Consequently, placental blood flow and vascular development are essential components of normal placental function and are critical to fetal growth and development. Normal fetal growth and development are important to ensure optimum health of offspring throughout their subsequent life course. In numerous sheep models of compromised pregnancy, in which fetal or placental growth, or both, are impaired, utero-placental blood flows are reduced. In the models that have been evaluated, placental vascular development also is altered. Recent studies found that treatments designed to increase placental blood flow can 'rescue' fetal growth that was reduced due to low maternal dietary intake. Placental blood flow and vascular development are thus potential therapeutic targets in compromised pregnancies.
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