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Uterine Vascular Control Preconception and During Pregnancy

Sara B. Fournier, Jeanine N. D'Errico, Phoebe A. Stapleton

10.1002/cphy.c190015

Source: Volume 11, Issue 3, July 2021

Published online: June 2021

Full Article on Wiley Online Library



Abstract

Successful pregnancy and reproduction are dependent on adequate uterine blood flow, placental perfusion, and vascular responsivity to fetal demands. The ability to support pregnancy centers on systemic adaptation and endometrial preparation through decidualization, embryonic implantation, trophoblast invasion, arterial/arteriolar reactivity, and vascular remodeling. These adaptations occur through responsiveness to endocrine signaling and local uteroplacental mediators. The purpose of this article is to highlight the current knowledge associated with vascular remodeling and responsivity during uterine preparation for and during pregnancy. We focus on maternal cardiovascular systemic and uterine modifications, endometrial decidualization, implantation and invasion, uterine and spiral artery remodeling, local uterine regulatory mechanisms, placentation, and pathological consequences of vascular dysfunction during pregnancy. © 2021 American Physiological Society. Compr Physiol 11:1871‐1893, 2021.

Figure 1. Figure 1. Uterine gross anatomy and blood supply. (A) Human uterus. View of the human female reproductive tract. Human uterine blood flow is derived from the ovarian and uterine arteries. These arteries branch to form the arcuate artery, allowing for greater tissue perfusion. The arcuate arteries subsequently branch to the radial artery, straight/basal arterioles, and spiral/preplacental arterioles. (B) Rodent uterus. The rodent uterus is a dual‐horn, bilateral organ allowing for multiple pup litters. The vascular architecture between the human and rodent uteri is very similar, making the rodent an ideal model to assess reproductive physiology. (C) Rabbit uterus. The rabbit also has a duplex uterus, with two independent uterine horns combining at the cervix to allow for multiple fetus litters. The vasculature is very similar to that of the rodent, with their main artery supply via the ovarian artery, with bifurcates to the ovarian and uterine branches, the uterine artery supplying the distal uterine horn, and the vaginal artery. Secondary arteries may form analogous to human arcuate arteries; arcuate and radial arteries provide blood supply to the myometrium and preplacental arterioles. (D) Sheep uterus. The sheep uterus consists of two conjoined cavities with a short uterine body. The vasculature is similar to that of humans with the main source of blood flow supplied by the uterine artery. The ovary is supplied by the ovarian artery. The uterine artery branches, giving rise to anastomose, which acts in a similar fashion to human arcuate arteries. These branches give rise to coiled secondary radial arteries that supply the myometrium and preplacental vessels.
Figure 2. Figure 2. Vasodilation during the estrous cycle and pregnancy. Vascular reactivity to endothelium‐dependent (A) or ‐independent (B) modulators of vascular smooth muscle relaxation varies during the phases of the rodent estrous cycle (black lines). Perturbations to maternal homeostasis through natural (e.g., circadian rhythm disturbances or noise pollution) or chemical (e.g., air or water pollution) exposures may make these variations more pronounced (red lines). Reprinted, with permission, from Stapleton PA, et al., 2018 207.
Figure 3. Figure 3. Decidualization. Representation of decidualization of the human endometrium. Morphological and functional differentiation of endometrial stromal cells (ESCs), especially during the implantation window, is required for successful pregnancy outcome. Reprinted, with permission, from Murakami K, et al., 2018 150.
Figure 4. Figure 4. Trophoblastic invasion. Trophoblast invasion and spiral artery remodeling in healthy pregnancy. Reprinted, with permission, from Soares MJ, et al., 2014 202.
Figure 5. Figure 5. Spiral artery remodeling. Spiral artery remodeling continues throughout pregnancy into the second and third trimesters to provide increased blood flow to the growing fetus. Pregnancies that suffer from ischemic placental disease may demonstrate shallow trophoblast invasion and defective vascular remodeling, thus leading to reduced maternal blood flow and compromised fetal growth. Reprinted, with permission, from Roberts JM, 2014 177.
Figure 6. Figure 6. Circulation of the intervillous space. Maternal blood enters the intervillous space from uterine spiral arteries and flows around terminal villi. After the exchange of oxygen and nutrients, the umbilical vein carries oxygenated and nutrient‐rich fetal blood to the fetal circulation. Reprinted, with permission, from Red‐Horse K, et al., 2005 172.
Figure 7. Figure 7. Uteroplacental blood flow. Schematic depicting the increase in uterine blood flow through gestation in response to fetal growth. Reprinted, with permission, from Greiss FC, et al., 1972 80.
Figure 8. Figure 8. Uteroplacental and fetoplacental circulation. The uterine, radial, and spiral arteries/arterioles perfuse the placenta with nutrient‐rich blood. The fetoplacental circulation includes the umbilical cord and the blood vessels within the placenta that carry fetal blood. Umbilical arteries carry deoxygenated and nutrient‐depleted fetal blood from the fetus to the villous core fetal vessels where the exchange of oxygen and nutrients takes place. The umbilical cord returns oxygenated and nutrient‐rich fetal blood to the fetal circulation. Adapted, with permission, from D'Errico JN, et al., 2019 47,48.
Figure 9. Figure 9. Uteroplacental growth. The uterine vasculature and muscle remodel significantly to sustain a successful pregnancy. This photograph shows the age‐matched uterine horn from pregnant (A) and nonpregnant (B) rats to depict vascular growth during pregnancy. Reprinted, with permission, from Mandala M and Osol G, 2012 129.
Figure 10. Figure 10. Uterine vascular hypertrophic remodeling. Vascular remodeling may be normal or pathologic. Hypertrophic vascular remodeling describes an increase in luminal wall thickness. This remodeling may be inward (i.e., narrowing the vascular lumen), eutrophic (i.e., maintaining luminal circumference), or outward (i.e., expanding the vascular lumen). The remodeling in the uterine circulation during gestation may be described as outward hypertrophic, thereby increasing both the wall area and the luminal cross section.
Figure 11. Figure 11. Uterine vascular reactivity. Local vascular responses are altered during pregnancy, shifting toward vascular smooth muscle (VSM) relaxation and subsequent vasodilation. This shift is depicted by (A) reduced responsiveness to phenylephrine, a vasoconstrictor, (B) heightened response to sodium nitroprusside, an endothelium‐independent vasodilator in arcuate arteries from pregnant rats compared to nonpregnant, and (C) no change in responsivity to acetylcholine, an endothelium‐dependent vasodilator between the arteries excised from pregnant and nonpregnant rats. Reprinted, with permission, from Fuller R, et al., 2011 62.


Figure 1. Uterine gross anatomy and blood supply. (A) Human uterus. View of the human female reproductive tract. Human uterine blood flow is derived from the ovarian and uterine arteries. These arteries branch to form the arcuate artery, allowing for greater tissue perfusion. The arcuate arteries subsequently branch to the radial artery, straight/basal arterioles, and spiral/preplacental arterioles. (B) Rodent uterus. The rodent uterus is a dual‐horn, bilateral organ allowing for multiple pup litters. The vascular architecture between the human and rodent uteri is very similar, making the rodent an ideal model to assess reproductive physiology. (C) Rabbit uterus. The rabbit also has a duplex uterus, with two independent uterine horns combining at the cervix to allow for multiple fetus litters. The vasculature is very similar to that of the rodent, with their main artery supply via the ovarian artery, with bifurcates to the ovarian and uterine branches, the uterine artery supplying the distal uterine horn, and the vaginal artery. Secondary arteries may form analogous to human arcuate arteries; arcuate and radial arteries provide blood supply to the myometrium and preplacental arterioles. (D) Sheep uterus. The sheep uterus consists of two conjoined cavities with a short uterine body. The vasculature is similar to that of humans with the main source of blood flow supplied by the uterine artery. The ovary is supplied by the ovarian artery. The uterine artery branches, giving rise to anastomose, which acts in a similar fashion to human arcuate arteries. These branches give rise to coiled secondary radial arteries that supply the myometrium and preplacental vessels.


Figure 2. Vasodilation during the estrous cycle and pregnancy. Vascular reactivity to endothelium‐dependent (A) or ‐independent (B) modulators of vascular smooth muscle relaxation varies during the phases of the rodent estrous cycle (black lines). Perturbations to maternal homeostasis through natural (e.g., circadian rhythm disturbances or noise pollution) or chemical (e.g., air or water pollution) exposures may make these variations more pronounced (red lines). Reprinted, with permission, from Stapleton PA, et al., 2018 207.


Figure 3. Decidualization. Representation of decidualization of the human endometrium. Morphological and functional differentiation of endometrial stromal cells (ESCs), especially during the implantation window, is required for successful pregnancy outcome. Reprinted, with permission, from Murakami K, et al., 2018 150.


Figure 4. Trophoblastic invasion. Trophoblast invasion and spiral artery remodeling in healthy pregnancy. Reprinted, with permission, from Soares MJ, et al., 2014 202.


Figure 5. Spiral artery remodeling. Spiral artery remodeling continues throughout pregnancy into the second and third trimesters to provide increased blood flow to the growing fetus. Pregnancies that suffer from ischemic placental disease may demonstrate shallow trophoblast invasion and defective vascular remodeling, thus leading to reduced maternal blood flow and compromised fetal growth. Reprinted, with permission, from Roberts JM, 2014 177.


Figure 6. Circulation of the intervillous space. Maternal blood enters the intervillous space from uterine spiral arteries and flows around terminal villi. After the exchange of oxygen and nutrients, the umbilical vein carries oxygenated and nutrient‐rich fetal blood to the fetal circulation. Reprinted, with permission, from Red‐Horse K, et al., 2005 172.


Figure 7. Uteroplacental blood flow. Schematic depicting the increase in uterine blood flow through gestation in response to fetal growth. Reprinted, with permission, from Greiss FC, et al., 1972 80.


Figure 8. Uteroplacental and fetoplacental circulation. The uterine, radial, and spiral arteries/arterioles perfuse the placenta with nutrient‐rich blood. The fetoplacental circulation includes the umbilical cord and the blood vessels within the placenta that carry fetal blood. Umbilical arteries carry deoxygenated and nutrient‐depleted fetal blood from the fetus to the villous core fetal vessels where the exchange of oxygen and nutrients takes place. The umbilical cord returns oxygenated and nutrient‐rich fetal blood to the fetal circulation. Adapted, with permission, from D'Errico JN, et al., 2019 47,48.


Figure 9. Uteroplacental growth. The uterine vasculature and muscle remodel significantly to sustain a successful pregnancy. This photograph shows the age‐matched uterine horn from pregnant (A) and nonpregnant (B) rats to depict vascular growth during pregnancy. Reprinted, with permission, from Mandala M and Osol G, 2012 129.


Figure 10. Uterine vascular hypertrophic remodeling. Vascular remodeling may be normal or pathologic. Hypertrophic vascular remodeling describes an increase in luminal wall thickness. This remodeling may be inward (i.e., narrowing the vascular lumen), eutrophic (i.e., maintaining luminal circumference), or outward (i.e., expanding the vascular lumen). The remodeling in the uterine circulation during gestation may be described as outward hypertrophic, thereby increasing both the wall area and the luminal cross section.


Figure 11. Uterine vascular reactivity. Local vascular responses are altered during pregnancy, shifting toward vascular smooth muscle (VSM) relaxation and subsequent vasodilation. This shift is depicted by (A) reduced responsiveness to phenylephrine, a vasoconstrictor, (B) heightened response to sodium nitroprusside, an endothelium‐independent vasodilator in arcuate arteries from pregnant rats compared to nonpregnant, and (C) no change in responsivity to acetylcholine, an endothelium‐dependent vasodilator between the arteries excised from pregnant and nonpregnant rats. Reprinted, with permission, from Fuller R, et al., 2011 62.
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Article Title: Uterine Vascular Control Preconception and During Pregnancy
 

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Sara B. Fournier, Jeanine N. D'Errico, Phoebe A. Stapleton. Uterine Vascular Control Preconception and During Pregnancy. Compr Physiol 2021, 11: 1871-1893. doi: 10.1002/cphy.c190015