Mechanisms of Endothelial Dysfunction in Pre-eclampsia and Gestational Diabetes Mellitus: Windows Into Future Cardiometabolic Health?

Abstract

Placental insufficiency and adipose tissue dysregulation are postulated to play key roles in the pathophysiology of both pre-eclampsia (PE) and gestational diabetes mellitus (GDM). A dysfunctional release of deleterious signaling motifs can offset an increase in circulating oxidative stressors, pro-inflammatory factors and various cytokines. It has been previously postulated that endothelial dysfunction, instigated by signaling from endocrine organs such as the placenta and adipose tissue, may be a key mediator of the vasculopathy that is evident in both adverse obstetric complications. These signaling pathways also have significant effects on long term maternal cardiometabolic health outcomes, specifically cardiovascular disease, hypertension, and type II diabetes. Recent studies have noted that both PE and GDM are strongly associated with lower maternal flow-mediated dilation, however the exact pathways which link endothelial dysfunction to clinical outcomes in these complications remains in question. The current diagnostic regimen for both PE and GDM lacks specificity and consistency in relation to clinical guidelines. Furthermore, current therapeutic options rely largely on clinical symptom control such as antihypertensives and insulin therapy, rather than that of early intervention or prophylaxis. A better understanding of the pathogenic origin of these obstetric complications will allow for more targeted therapeutic interventions. In this review we will explore the complex signaling relationship between the placenta and adipose tissue in PE and GDM and investigate how these intricate pathways affect maternal endothelial function and, hence, play a role in acute pathophysiology and the development of future chronic maternal health outcomes.

Keywords: GDM; PE; adiposity; endothelial dysfunction; mitochondria; oxidative stress; therapeutics.

Figure 1

Mechanisms linking placenta and adipose tissue dysfunction to endothelial damage. Aberrant endocrine organ dysfunction leads to excessive ROS generation and the release of inflammatory motifs from the placenta and adipose tissue. Deleterious motifs such as NLRP3 by-products, miRNA, inflammatory cytokines, and mtDNA enter the circulation, instigating various pathways which drive localized damage to the endothelium through inhibition of angiogenesis and inflammation. Sequential endothelial dysfunction ensues and pathogenic pathways such as TLR-4 driven cytokine production further upregulate ROS generation, creating a pernicious feedback loop. Maternal vasculopathy ensues, resulting in acute complications and poor chronic health outcomes. Created with BioRender.com. STB, syncytiotrophoblast; EV, extracellular vesicle; ROS, reactive oxygen species; GLUT-4, glucose transporter type 4; eNOS, endothelial nitric oxide synthase; MMP, matrix metallopeptidase; TLR-4, toll-like receptor 4; sFLT-1, soluble fms-like tyrosine kinase-1; miRNA, micro ribonucleic acid; cf-mtDNA, cell-free mitochondrial deoxyribonucleic acid; NLRP3, NOD-; LRR- and pyrin domain-containing protein 3; AGE, advanced glycation endproducts; oxLDL, oxidized low-density lipoprotein.

Figure 2

Schematic diagram of the pharmacodynamics of various proposed therapeutic interventions for endothelial damage prophylaxis. These agents can inhibit deleterious pathways upstream of endothelial cell dysfunction, potentially preventing the maternal clinical manifestations associated with pre-eclampsia and gestational diabetes mellitus. Created with BioRender.com. EV, extracellular vesicle; ROS, reactive oxygen species; DAMP, damage-associated molecular pattern; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NEK7, NIMA related kinase 7; NLRP3, NOD-; LRR,- and pyrin domain-containing protein 3; BHB, beta-hydroxybutyrate; IL, interleukin; AGE, advanced glycation end products; RAGE, receptor for AGE.