Role of nitric oxide in placental vascular development and function

Abstract

Nitric oxide (NO) is one of the most pleiotropic signaling molecules at systemic and cellular levels, participating in vascular tone regulation, cellular respiration, proliferation, apoptosis and gene expression. Indeed NO actively participates in trophoblast invasion, placental development and represents the main vasodilator in this tissue. Despite the large number of studies addressing the role of NO in the placenta, its participation in placental vascular development and the effect of altered levels of NO on placental function remains to be clarified. This review draws a time-line of the participation of NO throughout placental vascular development, from the differentiation of vascular precursors to the consolidation of vascular function are considered. The influence of NO on cell types involved in the origin of the placental vasculature and the expression and function of the nitric oxide synthases (NOS) throughout pregnancy are described. The developmental processes involved in the placental vascular bed are considered, such as the participation of NO in placental vasculogenesis and angiogenesis through VEGF and Angiopoietin signaling molecules. The role of NO in vascular function once the placental vascular tree has developed, in normal pregnancy as well as in pregnancy-related diseases, is then discussed.

Fig. 1

Schematic representation of NOS isoform expression in the placenta. Changes in total NOS (blue background), eNOS (red line) and iNOS (green line) expression in placenta throughout pregnancy. Graph shows NOS levels described for different species (i.e. human, mouse, porcine, rat and sheep) determined by enzymatic activity and/or protein expression. Data derived from Refs. [15–17, 19, 21–24, 184]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Nitric oxide-dependent vasodilation in the placenta. Vasodilator effects of NO in placental vessels can be induced via; a) activation of protein kinases (i.e. PKC, Akt and ERK1/2) by shear stress (SS), adenosine (Ado), ATP, VEGF or PlGF; and b) increasing intracellular calcium concentration induced by agonists (i.e. CGRP and histamine). Both pathways activate eNOS leading to NO production, which diffuses to the adjacent smooth muscle layer. Noteworthy, NO action on placental smooth muscle cells occurs either in a cGMP-dependent (PKG) and -independent (BK_Ca) fashion.

Fig. 3

Effects of acute hypoxia in placental vasculature. Depicted in this figure is the vascular response of placental (umbilical and chorionic) vessels to an acute reduction in oxygen levels.