Hypertension in pregnancy: Taking cues from pathophysiology for clinical practice

Abstract

Pregnancy-related hypertension (PHTN) syndromes are a frequent and potentially deadly complication of pregnancy, while also negatively impacting the lifelong health of the mother and child. PHTN appears in women likely to develop hypertension later in life, with the stress of pregnancy unmasking a subclinical hypertensive phenotype. However, distinguishing between PHTN and chronic hypertension is essential for optimal management. Preeclampsia (PE) is linked to potentially severe outcomes and lacks effective treatments due to poorly understood mechanisms. Inadequate remodeling of spiral uterine arteries (SUAs), the cornerstone of PE pathophysiology, leads to hypoperfusion of the developing placenta. In normal pregnancies, extravillous trophoblast (EVT) cells assume an invasive phenotype and invade SUAs, transforming them into large conduits. Decidual natural killer cells play an essential role, mediating materno-fetal immune tolerance, inducing early SUA remodeling and regulating EVT invasiveness. Notch signaling is important in EVT phenotypic switch and is dysregulated in PE. The hypoxic placenta releases antiangiogenic and proinflammatory factors that converge upon maternal endothelium, inducing endothelial dysfunction, hypertension, and organ damage. Hypoxia-inducible factor 1-α is upstream of such molecules, whereas endothelin-1 is a major effector. We also describe important genetic links and evidence of incomplete materno-fetal immune tolerance, with PE patients presenting with autoantibodies, lower T_reg , and higher T_h 17 cells. Thus, PE manifestations arise as a consequence of mal-placentation or/and because of a predisposition of the maternal vascular bed to excessively react to pathogenic molecules. From this pathophysiological basis, we provide current and propose future therapeutic directions for PE.

Keywords: Decidual Natural Killer Cells; Extravillous Trophoblast Cells; Hypoxia; Incomplete Materno-Fetal Immune Tolerance; Preeclampsia.

Figure 1

Role of decidual natural killer cells (DNKs) in placentation and preeclampsia pathology. In normal pregnancy, DNKs adopt a regulatory natural killer cell (RNK) phenotype to mediate spiral uterine artery (SUA) remodeling both directly and indirectly. In pathologic hypoxia, DNKs adopt a cytolytic phenotype. DNKs also mediate materno‐fetal immune tolerance by interacting with CD4+ cells. Preeclampsia is associated with increased Th₁₇ cells and decreased T regulatory cells, compared with normal pregnancies. Abbreviations: CNK, cytolytic natural killer cell; FUGR, fetal intrauterine growth restriction; MAP, mean arterial pressure; MMP, matrix metalloproteinase; VSMC, vascular smooth muscle cell

Figure 2

(a) Molecular pathways linking placental hypoxia to generalized endothelial dysfunction. (b) Infusing sFlt‐1, sEng, and the combination of sFlt‐1 and sEng recapitulates the clinical preeclampsia (PE) syndrome. Abbreviations: AA‐AT1, activating auto‐antibody against angiotensin 1 receptor; ET‐1, endothelin 1; FUGR, fetal intrauterine growth restriction; HELLP, hemolysis, elevated liver enzymes, and low platelets; HIF1‐ α, hypoxia‐inducible factor 1‐α; PE, preeclampsia; sEng, soluble endoglin; sFlt‐1, soluble receptor for VEGF and PIGF; SUA, spiral uterine artery; TGFβ, transforming growth factor β; TNFα, tumor necrosis factor α