Flow-Written Endothelial Memory Governs Regional LDL Import Competence in Early Atherosclerosis

ABSTRACT Atherosclerotic cardiovascular disease remains the leading cause of mortality worldwide, yet the mechanisms governing the spatial initiation of atherosclerotic plaques remain incompletely explained by circulating lipid burden alone. While elevated levels of apolipoprotein B (ApoB)–containing lipoproteins are necessary for plaque formation, plaque initiation occurs in highly localized arterial regions rather than uniformly across the vasculature. This spatial heterogeneity suggests the presence of a regulatory endothelial state variable that determines whether circulating lipoproteins are permitted to enter and accumulate within the arterial wall. Here we propose a unified mechanistic framework in which early atherosclerosis is governed by a previously unformalized control variable termed Regional LDL Import Competence (RLIC). RLIC represents the dynamic capacity of the arterial endothelium to import ApoB-containing lipoproteins into the intimal space. Within this model, plaque initiation is determined not solely by systemic ApoB concentration but by the interaction between ApoB exposure and the local endothelial import state. We therefore describe plaque initiation pressure as the product of systemic lipoprotein substrate availability and regional endothelial import competence. We further propose that RLIC is not a static property but a dynamic endothelial state that exhibits bistability and hysteresis. Endothelial cells transition between a protective anti-atherogenic state and an import-competent state permissive to lipoprotein entry. This transition is governed by hemodynamic forces, inflammatory amplification, and protective transcriptional reserves centered on the KLF2/KLF4 regulatory axis. Persistent endothelial state transitions are hypothesized to arise through chromatin-level memory written by disturbed-flow mechanotransduction pathways. In this framework, disturbed flow activates the mechanosensitive ion channel Piezo1, which propagates signaling through integrin–FAK/Src–YAP pathways and chromatin remodeling mechanisms including the histone demethylase KDM5B. These pathways encode endothelial memory that stabilizes the import-competent phenotype. Complementary epigenetic marks, including KLF4 promoter methylation and flow-sensitive super-enhancer remodeling, may reinforce this transcriptional reprogramming. Upstream of these mechanotransduction events lies the endothelial glycocalyx, a structural mechanosensing interface that regulates shear force transmission to endothelial signaling systems. Glycocalyx degradation is proposed to impair laminar flow sensing and bias endothelial signaling toward disturbed-flow pathways, thereby weakening the protective KLF2/KLF4 reserve and facilitating persistent endothelial dysfunction. Integrating vascular biomechanics, lipoprotein biology, endothelial epigenetics, and systems modeling, this framework conceptualizes early atherosclerosis as a state transition in endothelial mechanosensing rather than solely a consequence of circulating lipid burden. Within this model, plaque initiation emerges from the interaction between ApoB particle exposure and a locally persistent endothelial import state governed by mechanosensory integrity and chromatin memory. This systems-level hypothesis generates multiple experimentally testable predictions, including that persistent suppression of protective endothelial transcriptional programs should precede plaque initiation at disturbed-flow arterial segments and that modulation of mechanotransduction or chromatin-writing pathways should alter the endothelial import state independent of systemic lipid concentrations. By introducing Regional LDL Import Competence as a formal control variable, this model provides a unifying framework for understanding plaque localization, disease persistence, and variability in cardiovascular risk among individuals with similar lipid profiles. This work proposes a conceptual mechanistic framework and generates experimentally testable hypotheses regarding endothelial mechanosensing and lipoprotein transport in early atherosclerosis. KEYWORDS Atherosclerosis Apolipoprotein B (ApoB) Low-density lipoprotein (LDL) Endothelial mechanotransduction Regional LDL Import Competence (RLIC) Disturbed flow Piezo1 KDM5B KLF2/KLF4 Endothelial glycocalyx Chromatin memory Hemodynamics Plaque initiation Vascular biology Cardiovascular disease