Endothelin-1 and the Fibrinolytic System in Obesity: A Mechanistic Account of Hypofibrinolysis and Cardiometabolic Risk

Obesity shifts the hemostatic balance toward fibrin persistence. Plasma plasminogen activator inhibitor-1 (PAI-1) rises with visceral fat, tissue plasminogen activator (t-PA) activity falls, and clot lysis time lengthens, a pattern that predicts myocardial infarction, ischemic stroke and venous thromboembolism independently of lipids and glycemia. Endothelin-1 (ET-1) is a candidate upstream driver of this shift. ET-1 is overproduced in obesity and insulin resistance; its vasoconstrictor tone is measurably higher in people with excess adiposity, and in cultured vascular smooth muscle, endothelial and mesangial cells, it raises PAI-1 transcription while suppressing t-PA release. The same stimuli that drive adipose PAI-1 output, including insulin, tumor necrosis factor-α, interleukin-6, leptin, angiotensin II, glucocorticoids and hyperglycemia, also induce preproendothelin-1, so the two systems are regulated in parallel and converge in cultured vascular cells, where ET-1 directly induces PAI-1. This hierarchy has not been demonstrated in human adipose tissue. The translational picture is less tidy. Acute forearm infusion of ET-1 in healthy humans does not alter regional t-PA or PAI-1 release, which excludes an acute secretory mechanism in healthy vasculature and leaves a chronic transcriptional mechanism as the remaining possibility, untested in either healthy or obese humans. This review traces the endothelin system from gene to receptor, summarizes the components of fibrinolysis that obesity disturbs, and assembles the cellular and clinical evidence that links the two, labeling each claim by the species and preparation that supports it. It then examines interventions that move both axes, including weight loss, bariatric surgery, exercise training, metformin, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, endothelin receptor antagonists and small-molecule PAI-1 inhibitors. Several questions remain open, among them whether endothelin receptor blockade lowers PAI-1 in people with obesity, whether ETA and ETB receptors act in opposite directions on fibrinolysis, and whether hypofibrinolysis is reversible once adipose fibrosis is established.