Extracorporeal life support has become a widely integrated tool in treating refractor cardiopulmonary failure. Under normal physiologic conditions, arterial blood flow is inherently pulsatile, and cyclic shear stress plays a pivotal role in maintaining endothelial homeostasis and vascular integrity. In contrast, contemporary ECMO systems generate continuous, non-pulsatile flow, representing a fundamental deviation from native hemodynamics. While non-pulsatile ECMO pumps remain the clinical standard for their reliability and ease of use, their non-physiologic approach to augmenting perfusion is increasingly recognized as a detriment to vascular health. Continuous-flow disrupts numerous signaling and regenerative pathways integral to endothelial proliferation. Through culminative dysregulation of nitric oxide expression, pathological angiogenesis, and accelerated denudation of von Willibrand Factor, patients experience heightened risk of hemorrhagic complications, while thrombotic and embolic events arise through other distinct mechanisms. This review aims to centralize current evidence regarding vascular health to identify causative agents of endothelial insult associated with non-pulsatile VA-ECMO. We further summarize experimental and clinical studies discussing the impact of altered shear forces and their contribution to endothelial dysregulation.