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Under pressure: Pressure loads can modify endothelial cell flow responses

ABSTRACT: Blood flow within the vasculature is a critical determinant of endothelial cell (EC) identity and functionality, yet the intricate interplay of various hemodynamic forces and their collective impact on endothelial and vascular responses are not fully understood. Specifically, the role of hydrostatic pressure in the context of flow response is understudied, despite its known significance in vascular development and disease progression. To address this gap, we developed in vitro models to investigate how pressure influences EC responses to flow. Our study demonstrates that elevated pressure conditions significantly modify shear-induced flow alignment and increase endothelial cell density, a phenomenon often observed in vascular diseases. Utilizing both bulk and single-cell RNA sequencing, we found that while flow is the primary driver of transcriptional changes from static conditions, pressure distinctly modulates this flow response by upregulating gene sets linked to arterial cell phenotypes. When compared to early vascular development stages, pressure was notably associated with gene sets that promote the formation of early hemogenic endothelial cells. Our findings emphasize the necessity of an integrative approach to endothelial cell mechanotransduction, one that encompasses the effects induced by pressure alongside other hemodynamic forces.

ORGANISM(S): Homo sapiens

PROVIDER: GSE260600 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Background: Hemodynamic forces exert a profound influence on endothelial cell signaling and, when abnormal, contribute centrally to human vascular disease. Pulmonary arterial hypertension (PAH) is characterized by both hemodynamic derangement and pulmonary arterial endothelial cell (PAEC) dysfunction. Despite importance in disease initiation and progression, the combined effects of shear and pressure forces on PAEC biology remain incompletely understood, particularly in the context of PAH. Methods: PAECs obtained at explant from controls and from patients with idiopathic or congenital heart disease-associated PAH (CHD-PAH) were cultured in a custom resistor-coupled microfluidic platform and exposed to static, low (3 dyne/cm²), or high (20 dyne/cm²) shear stress under either low or elevated (60 mmHg) pressure. After 24 hours, we assessed cellular morphology and performed systems-level transcriptomic analysis via bulk RNA sequencing, incorporating analyses of PAH subtype and donor sex. Results: PAECs (n=18 donors) aligned with flow under high, but not low, shear, and alignment was not significantly altered by disease state or pressure. Shear stress fundamentally reorganized the PAEC transcriptome and the “dose-response” to increasing shear differed across biological pathways in six statistically significant patterns. Increasing shear led to divergence in transcription between control and PAH cells, particularly in pathways involved in immune activation, stress signaling, and vascular remodeling, with subtype differences also observed. Pressure alone had modest effects on transcription, though CHD-PAH PAECs especially displayed pressure-induced stress and inflammatory signaling. We identified sexual dimorphism in the endothelial shear response, noting male cells under shear enriched for pathways involved in proliferation and inflammation and female cells enriched for lipid metabolism and stress responses. Conclusions: Shear and pressure forces profoundly influence PAEC transcription, with responses shaped by disease state, PAH subtype, and sex. These findings highlight the need for further investigation into mechanosensitive pathways in PAH as potential targets for novel therapies.

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Under pressure: Pressure loads can modify endothelial cell flow responses

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