Biology subjects

Fallon, M. B.

Publications and source records attributed to Fallon, M. B..

4 recordsLinked to original sources

bioRxiv2026

E2F1 Drives Endothelial Arterial Programming in Pulmonary Arterial Hypertension

BackgroundPulmonary arterial hypertension (PAH) is driven by maladaptive endothelial remodeling, but the transcriptional regulators that couple proliferative stress to arterialized endothelial states remain incompletely defined. E2F transcription factor 1 (E2F1) is classically viewed as a cell-cycle regulator; whether E2F1 functions as a disease-driving node that promotes endothelial arterial programming in PAH remains unknown. MethodsWe integrated human PAH lung transcriptomic analyses, deconvolution-based endothelial-state scoring, and complementary mouse and rat PH models with bulk RNA-seq, single-cell RNA-seq, pseudotime analysis, and CellChat inference. E2F1 function was tested using adenoviral E2F1 overexpression, pharmacological pan-E2F inhibition with HLM006474, and genetic E2f1 loss on a tamoxifen-inducible endothelial Egln1-deletion background. ResultsIn PAH lungs, E2F1 was increased and arterial endothelial cell (AEC) fraction and expanded arterial program scores were elevated. Similarly, Egln1Tie2Cre lungs showed increased E2F1, induction of arterial remodeling genes, and activation of an E2F target program. Genetic loss of E2f1 reduced right ventricle systolic pressure, right ventricle hypertrophy, vascular remodeling, and distal muscularization in Egln1-driven PH mice model. Bulk RNA-seq showed suppression of E2F, mitotic, epithelial mesenchymal transition, and extracellular matrix-remodeling programs. Single-cell RNA-seq showed reduced AEC accumulation, normalized CAP1/CAP2 distribution, and reduced progression along the CAP1-AEC trajectory. CellChat analysis identified loss of an arterial communication hub, including reduced ECM, VEGF, and Notch signaling when E2F1 is loss. Conversely, E2F1 overexpression in human lung microvascular ECs increased proliferation, activated E2F/cell-cycle and Notch/arterial programs. Pharmacological inhibition of E2F via HLM006474 suppressed endothelial proliferation and attenuated Egln1-driven and MCT-induced PH, including reversal of established MCT-PH. ConclusionsE2F1 acts as a disease-relevant transcriptional factor linking endothelial cell-cycle activation to arterial programming, matrix and angiogenic communication programs, and pulmonary vascular remodeling. Genetic or pharmacological E2F inhibition mitigates experimental PH, supporting E2F1 as a therapeutic target in PAH. Clinical Perspective What is new?1. This study identifies E2F1 as a previously unrecognized driver of PAH rather than only a downstream marker of cell-cycle activation. 2. Genetic loss of E2f1 rescues hemodynamic and structural features of Egln1-driven PAH, and pharmacological E2F inhibition attenuates both Egln1-driven and monocrotaline-induced PH. 3. Mechanistically, E2F1 links endothelial proliferation to Notch-associated arterial programming, AEC accumulation, and CAP1-to-iAEC-to-AEC trajectory progression. What are the clinical implications?1. E2F1 defines a tractable transcriptional node that integrates proliferative stress with arterial endothelial reprogramming, a core pathological feature of PAH vascular remodeling. 2. Pan-E2F small-molecule inhibitors, several of which are in development for oncology, may be repurposable for PAH if E2F1-dependent endothelial arterial-programming signatures identify responsive disease states. 3. Plasma- or tissue-based readouts of E2F1 activity may identify PAH patients most likely to benefit from E2F-directed therapy.

physiology↗

bioRxiv2025

Liver angiocrine myeloid-derived growth factor protects against endothelial dysfunction in pulmonary arterial hypertension

Myeloid-derived growth factor (MYDGF) is a hepatic angiokine with protective effects in systemic vascular beds, but its role in pulmonary arterial hypertension (PAH) is unknown. We hypothesized that hepatic MYDGF deficiency contributes to pulmonary endothelial activation in PAH and that recombinant MYDGF could rescue endothelial injury. In the Sugen-hypoxia (SuHx) rat model, hepatic MYDGF expression was decreased, while pulmonary vascular cell adhesion molecule-1 (VCAM-1) expression was increased. Human hepatic sinusoidal endothelial cells exposed to pro-inflammatory macrophage conditioned media downregulated MYDGF, and recombinant MYDGF restored pulmonary artery endothelial cell resistance to inflammatory activation via MAP4K4-NF{kappa}B signaling. In the Brown University PHiNE PAH cohort (n=41 PAH, n=27 controls), plasma proteomics demonstrated increased MYDGF in PAH patients compared with controls, but MYDGF levels declined with worsening liver stiffness and correlated with higher pulmonary vascular resistance. In the independent Servetus PAH cohort (n=117), higher plasma MYDGF was associated with mortality and right ventricular dilation. Together, these findings demonstrate hepatic MYDGF deficiency in experimental PAH, tissue specificity of endothelial MYDGF to the liver, and MYDGFs potential to mitigate pulmonary endothelial inflammation. However, human data suggest a paradoxical association of elevated circulating MYDGF with adverse outcomes, underscoring the complex biology of angiogenic growth factors in PAH. MYDGF may represent a novel hepatic angiokine linking systemic inflammation, liver dysfunction, and pulmonary vascular disease.

molecular biology↗

bioRxiv2024

General Capillary Endothelial Cells Undergo Reprogramming into Arterial Endothelial Cells in Pulmonary Hypertension through HIF-2a/Notch4 Pathway

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature death. The underlying mechanisms of loss of distal capillary endothelial cells (ECs) and obliterative vascular lesion formation remain unclear. Our recent single-cell RNA sequencing, spatial transcriptomics analysis, RNASCOPE, and immunostaining analysis showed that arterial ECs accumulation and loss of capillary ECs were evident in human PAH patients and pulmonary hypertension (PH) rodents. Pseudotime trajectory analysis of the single-cell RNA sequencing data suggest that lung capillary ECs transit to arterial ECs during the development of PH. Our study also identified CXCL12 as the marker for arterial ECs in PH. Capillary EC lineage tracing approach using capillary specific-Dre;Tdtomato reporter mice demonstrated that capillary ECs gave rise to arterial ECs during PH development. Genetic deletion of HIF-2a or pharmacological inhibition of Notch4 normalized the arterial programming in PH. In conclusion, our study demonstrates that capillary endothelium transits to arterial endothelium through the HIF-2a-Notch4 pathway during the development of PAH. Thus, targeting arterial EC transition might be a novel approach for treating PAH patients.

physiology↗

bioRxiv2024

Endothelial fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Single-cell RNA sequencing (scRNAseq) analysis found that both FABP4 and FABP5 were highly induced in endothelial cells (ECs) of Egln1Tie2Cre (CKO) mice, which was also observed in pulmonary arterial ECs (PAECs) from idiopathic PAH (IPAH) patients, and in whole lungs of pulmonary hypertension (PH) rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters using plasma proteome analysis. Genetic deletion of both Fabp4 and 5 in CKO mice (Egln1Tie2Cre/Fabp4-5-/-, TKO) caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure assessed by echocardiography, hemodynamic and histological analysis. Employing bulk RNA-seq and scRNA-seq, and spatial transcriptomic analysis, we showed that Fabp4/5 deletion also inhibited EC glycolysis and distal arterial programming, reduced ROS and HIF-2 expression in PH lungs. Thus, PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.

molecular biology↗