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

Description

Abstract

DESCRIPTION

Atherosclerotic cardiovascular disease is characterized by the focal accumulation of lipids, inflammatory cells, and extracellular matrix within the arterial wall. Although elevated circulating levels of apolipoprotein B (ApoB)–containing lipoproteins are a necessary driver of atherosclerosis, plaque formation occurs in highly localized arterial regions rather than uniformly across the vascular tree. Classical models attribute this spatial distribution primarily to hemodynamic factors such as disturbed blood flow at arterial bifurcations and curvatures. However, these models do not fully explain why plaque initiation requires both elevated lipoprotein burden and specific endothelial conditions that permit lipoprotein entry into the arterial intima.

In this manuscript we propose a systems-level mechanistic framework in which early atherosclerosis is governed by a previously underdefined endothelial state variable termed Regional LDL Import Competence (RLIC). RLIC represents the dynamic capacity of a specific arterial segment to internalize and transport ApoB-containing lipoproteins from circulation into the subendothelial space. Within this framework, plaque initiation is determined not solely by circulating lipid concentrations but by the interaction between systemic lipoprotein exposure and the local endothelial import state.

The proposed model conceptualizes plaque initiation pressure as the product of systemic ApoB burden and regional endothelial import competence. This formulation provides a mechanistic explanation for the long-recognized spatial heterogeneity of atherosclerotic lesions and for the observation that individuals with similar lipid levels may exhibit markedly different plaque burdens.

We further propose that RLIC represents a dynamic endothelial state exhibiting bistability and hysteresis. Endothelial cells transition between a protective anti-atherogenic state characterized by laminar-flow–induced transcriptional programs and an import-competent state permissive to lipoprotein entry and inflammatory signaling. These states are governed by hemodynamic forces, inflammatory amplification, and protective transcriptional reserves centered on the KLF2/KLF4 regulatory axis.

Persistent transitions into the import-competent state are hypothesized to arise through chromatin-level memory encoded by disturbed-flow mechanotransduction pathways. In particular, activation of the mechanosensitive ion channel Piezo1 under disturbed shear conditions propagates signaling through integrin–FAK/Src–YAP pathways and chromatin-modifying enzymes such as the histone demethylase KDM5B. These signaling cascades may encode endothelial memory that stabilizes pro-atherogenic transcriptional states.

Complementary epigenetic mechanisms including promoter methylation of the protective transcription factor KLF4 and remodeling of flow-sensitive super-enhancer landscapes may further reinforce this transcriptional reprogramming. Together, these processes provide a plausible biological substrate for the persistence of endothelial dysfunction even after transient mechanical or inflammatory insults.

Upstream of these signaling pathways lies the endothelial glycocalyx, a specialized carbohydrate-rich layer that mediates mechanosensing of hemodynamic forces. The glycocalyx regulates shear force transmission to endothelial mechanosensors including ion channels, integrins, and cytoskeletal complexes. Degradation of the glycocalyx is therefore predicted to impair laminar flow sensing and bias endothelial signaling toward disturbed-flow pathways, weakening protective transcriptional programs and facilitating the establishment of the import-competent endothelial state.

By integrating vascular biomechanics, lipoprotein transport biology, endothelial epigenetics, and systems modeling, this framework reconceptualizes early atherosclerosis as a state transition in endothelial mechanosensing rather than solely a function of circulating lipid levels. Within this model, plaque initiation arises from the interaction between ApoB particle exposure and a locally persistent endothelial state determined by mechanosensory integrity and chromatin-level memory.

This hypothesis generates multiple experimentally testable predictions. These include the expectation that persistent suppression of protective endothelial transcriptional programs should precede plaque initiation at disturbed-flow arterial segments, that modulation of mechanotransduction or chromatin-writing pathways should alter endothelial import competence independently of systemic lipid concentrations, and that restoration of endothelial mechanosensing fidelity may represent a therapeutic strategy for preventing early plaque formation.

By formalizing Regional LDL Import Competence as a control variable governing lipoprotein entry into the arterial wall, this work provides a conceptual framework linking hemodynamics, endothelial state transitions, and lipid-driven vascular disease. The proposed model offers a unifying perspective on plaque localization, disease persistence, and heterogeneity in cardiovascular risk among individuals with comparable systemic lipid profiles.