Challenges posed to the maternal circulation by pregnancy

Abstract

In primates, adequate growth of the fetus depends on the development of the uteroplacental unit. On the fetal side, this is achieved by the creation of the vascular network of the placenta. On the maternal side, the transformation of the spiral arteries into saccular nonreactive vessels by the trophoblast provides high blood flow to the intervillous space. Apart from the changes in the uterine arteries, the mother expands her plasma volume - at the expense of stimulating the renin-angiotensin-aldosterone system - and her cardiac output. In the maintaining of normotension in the face of an increased cardiac output and plasma volume, the renin-angiotensin-aldosterone system requires an enhanced vasodilator synthesis. Finally, in the late stages of pregnancy, a normal endothelial function is required to provide an ample margin to the activation provoked by deportation of syncytiotrophoblast fragments/factors to the maternal circulation. These four adaptative processes require various interrelated vasodilator systems. Deficient adaptations cause isolated or proteinuric arterial hypertension, intrauterine growth restriction, preterm delivery, and stillbirths, among others. Moreover, a normal or a defective adaptation to pregnancy influences maternal cardiovascular health in later life, as evidenced by various studies, most of them epidemiological; thus, pregnancy is now considered a stress test to the maternal cardiovascular system. Because of this, women planning to become pregnant should be screened for clinical and biochemical cardiovascular risks. Inversely, women presenting with hypertension in pregnancy should be thoroughly studied to detect and correct cardiovascular risks. The incorporation of the predictive value of a hypertensive pregnancy should help reduce cardiovascular disease in women.

Keywords: RAS; VEGF; kallikrein-kinin system; prostanoids; renin-angiotensin-aldosterone system.

Figure 1

Interactions between the different vasodilator systems. Note: Inhibitory pathways = arrows interrupted by oblique lines. Adapted from Valdés G, Kaufmann P, Corthorn J, Erices R, Brosnihan KB, Joyner-Grantham J. Vasodilator factors in the systemic and local adaptations to pregnancy. Reprod Biol Endocrinol. 2009;7:79 with permission of the publisher, BioMed Central. Abbreviations: ACE, angiotensin converting enzyme; AT-1-R, angiotensin II type 1 receptor; AT-2-R, angiotensin II type 2 receptor; B2R, bradykinin 2 receptor; eNOS, endothelial nitric oxide synthase; Flk, fetal liver kinase 1; Mas-R, Mas receptor; NO, nitric oxide; PGH₂, prostaglandin H₂; VEGF, vascular endothelial growth factor; VEGF-R2, VEGF receptor 2.

Figure 2

Diagram of the uteroplacental interface, showing its main cell types and the vasodilator repertoire of each type. The discontinuous yellow line depicts the path of trophoblasts that detach from the anchoring column to migrate through the uterine stroma, destroy the vascular smooth muscle, and colonize the lumen of the spiral arteries. Note: Adapted from Valdés G, Kaufmann P, Corthorn J, Erices R, Brosnihan KB, Joyner-Grantham J. Vasodilator factors in the systemic and local adaptations to pregnancy. Reprod Biol Endocrinol. 2009;7:79 with permission of the publisher, BioMed Central. Abbreviation: NK, natural killer.

Figure 3

Diagram showing the relation between the placenta and the maternal endothelium, in ischemic conditions, increased placental mass, and underlying cardiovascular risks. The microphotographs of the placental villi show syncytial knots prior to being deported into the maternal circulation (orange circles). In addition, the placenta sheds factors to the maternal circulation (green stars: sFLT-1, agonist autoantibodies to the AT-1-R, ADMA, and reactive oxygen species). Both syncytiotrophoblast microparticles and the soluble factors provoke endothelial dysfunction in pregestational healthy (smooth borders) or dysfunctional endothelial cells (spiky borders). Pregestational endothelial dysfunction also hinders uterine artery transformation (red broken arrow). Abbreviations: ADMA, asymmetric dimethylarginine; AT-1-R, angiotensin II type 1 receptor; sFLT-1, soluble fms-like tyrosine kinase 1.

Figure 4

Balance of factors that determine an adequate or defective adaptation to pregnancy in the maternal hemodynamics and in the development and maintenance of the uteroplacental unit, based on the equilibrium initially proposed for PGI₂ and TXA. The modulation of the maternal immune reaction and the state of the maternal vasculature have also been included, because though not analyzed in this review, they influence the adaptation to pregnancy. Note: Adapted from Valdés G, Kaufmann P, Corthorn J, Erices R, Brosnihan KB, Joyner-Grantham J. Vasodilator factors in the systemic and local adaptations to pregnancy. Reprod Biol Endocrinol. 2009;7:79 with permission of the publisher, BioMed Central. Abbreviations: ADMA, asymmetric dimethylarginine; AT-1-R, angiotensin II type 1 receptor; AT-1, angiotensin II type 1; AT-2, angiotensin II type 2; B2R, bradykinin 2 receptor; KDR, kinase domain receptor; FLT-1, fms-like tyrosine kinase 1; NO, nitric oxide; sFLT-1, soluble fms-like tyrosine kinase 1; VEGF, vascular endothelial growth factor.