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Pressure Points: Endothelial Responses to Hemodynamic Stress in Health and Pulmonary Arterial Hypertension

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303084 | GEO | 2025/08/14

REPOSITORIES: GEO

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			Action	DRS
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	GSE303084_GeneCounts1.tsv.gz	Tabular
	GSE303084_GeneCounts2.tsv.gz	Tabular

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Project description:Blood flow promotes emergence of definitive hematopoietic stem cells (HSCs) in the developing embryo, yet the signals generated by hemodynamic forces that influence hematopoietic potential remain poorly defined. In transplantation assays of hematopoietic reconstitution, we find that fluid shear stress endows long-term multilineage engraftment potential upon early hematopoietic tissues at E9.5 not previously described to harbor HSCs. Effects on hematopoiesis appear to be mediated in part by prostaglandin E2 (PGE2) and the cyclic AMP-protein kinase A (cAMP-PKA) signaling axis. Studies of Ncx1 cardiac mutants corroborate that blood flow is required for sufficient COX2 levels and phosphorylation of CREB. Further implicating PGE2 in mediating the effects of shear stress, we find that E10.5 and E11.5 AGM treated transiently with the synthetic analog dmPGE2 engraft more robustly and contribute to greater lymphoid reconstitution. These data provide a mechanism by which biomechanical forces induced by blood flow modulate hematopoietic potential. - AGM from C57BL/6J embryos at 10.5 days gestation (E10.5) were isolated by microdissection from uteri of pregnant dams, following by gentle dissociation by Accutase with agitation at room temperature for 20 minutes. Single cell suspension was seeded on microfluidic IBIDI VI^0.4 6-channel slides (0.8 to 1x10^7 cells per channel) and permitted to attach for 8 hours. Fluid movement was then applied to each channel using a Harvard Apparatus PHD ULTRA programmable syringe pump for manangement of M5300 Myelocult medium. Cells were exposed either to static/low flow (0.0001 dyne/cm^2) or wall shear stress (WSS) of 5 dyne/cm^2 for 6 hours or 36 hours. In addition, some cells were treated with 10 uM indomethacin (indo) to inhibit COX2 activity and PGE2 synthesis. Upon collection of cells with RLT lysis buffer (QIAGEN RNeasy kit), six channels of identical treatment were pooled to comprise a single sample. 24 samples total are included in this study. 12 samples were collected after 6 hours and 12 after 36 hours. In detail, samples included at 6 hours: 3 static, 3 static with indo, 3 WSS, 3 WSS with indo; and at 36 hours: 3 static, 3 static with indo, 3 WSS, 3 WSS with indo. Sample labels begin with the timepoint collected and end with the replicate number, i.e., 06WSS1 for the 6 hour collection of the first replicate of the WSS sample.

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Pressure Points: Endothelial Responses to Hemodynamic Stress in Health and Pulmonary Arterial Hypertension

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