Natoli, A. | Search bioRxiv

bioRxiv2026

VPS34 regulation in pulmonary arterial vascular smooth muscle cells in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is characterized by the hyperproliferative phenotype of pulmonary arterial smooth muscle cells (PAVSMCs) and extensive extracellular matrix (ECM) remodeling. Vacuolar protein sorting 34 (VPS34), a Class III Phosphatidylinositol-3 Kinase (PI3K), regulates cell proliferation, but its specific function in pulmonary vascular remodeling remains poorly understood. We aim to determine the role of VPS34 activation and regulation in PAVSMC proliferation, matrix deposition, and the progression of PAH. First, we found a marked decrease in the inhibitory phosphorylation of VPS34 at Ser164 (P-S164-VPS34), indicative of constitutive VPS34 activation, in remodeled pulmonary arteries (PAs) from human PAH patients and male mice exposed to Sugen/Hypoxia (SuHx). In human PAH PAVSMCs, siRNA-mediated knockdown of VPS34 or pharmacological inhibition via the selective inhibitor SAR405 significantly blunted cell proliferation and reduced the production of fibronectin, a major component of the remodeled ECM. Mechanistically, we found that Akt activation in PAH PAVSMCs promotes VPS34 activation; Protein Phosphatase 1 Catalytic Subunit Alpha is a potential effector in VPS34 activation; and active VPS34 led to the activation of the mTOR/S6 signaling pathway with tuberous sclerosis complex 2 downregulation. Finally, in vivo treatment with SAR405 attenuated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in SuHx mice, while concurrently decreasing vascular fibronectin deposition. Our study demonstrates that VPS34 activation, driven by an Akt-mediated loss of the inhibitory P-S164, is crucial in PAVSMC proliferation and fibrotic vascular remodeling in PAH. Targeting the VPS34 axis represents a promising anti-remodeling therapeutic strategy for the treatment of PAH. Keywords: Pulmonary arterial hypertension, vacuolar protein sorting 34, pulmonary vascular remodeling, pulmonary arterial vascular smooth muscle

cell biology↗

bioRxiv2026

Socotra Cormorants in the Arabian Gulf represent a large, but isolated population with low genetic diversity

The Socotra Cormorant (Phalacrocorax nigrogularis) is a threatened seabird endemic to the coastal areas of the Arabian Gulf and the Arabian Sea, two regions separated by the Strait of Hormuz. Conserving threatened species requires clear delineation of population boundaries and the evaluation of genetic diversity. However, information on population structure and genetic variation, necessary for such an assessment, is lacking for the Socotra Cormorants. In this study, we assessed population structure and genetic diversity of Socotra Cormorants using two contrasting genetic markers: (1) maternally inherited mtDNA cytochrome oxidase 1 (COI) and (2) a nuclear non-coding region, {beta}-fibrinogen intron 7 (FIB7). A total of 279 individuals were sampled from four colonies in the Arabian Gulf and one colony on Hasikiyah Island in the Arabian Sea. Findings based on COI-variation suggest that the Arabian Gulf colonies represent one large population with extensive gene flow between Gulf colonies--except for the most distant pair of colonies--but isolated from Hasikiyah in the Arabian Sea. COI-variation indicated significant differentiation between the colonies inside the Gulf and the Hasikiyah colony. This is consistent with the reported distribution patterns, and may reflect phylogeographic processes of the region. The Gulf population showed substantially lower COI-diversity, with significantly lower nucleotide and haplotype diversity compared to Hasikiyah. In contrast, FIB7 results indicated extensive connectivity among colonies, with no detectable population structure or significant differences between the Gulf population and Hasikiyah. This study presents the first characterization of population structure and genetic diversity of Socotra Cormorants. The low genetic diversity coupled with relative isolation of the Gulf Socotra Cormorants raises conservation concerns regarding their long-term viability by potentially reducing fitness and eroding their evolutionary capacity to adapt to environmental change. LAY SUMMARYO_LIThe Socotra Cormorant is a threatened seabird found in the Arabian Gulf and Arabian Sea, but little was previously known about its population structure and genetic diversity. C_LIO_LIWe analyzed 279 birds from five nesting colonies (4 in the Gulf and 1 in the Arabian Sea), using two genetic markers to assess population connectivity and variation. C_LIO_LIWe found that the Socotra cormorants inside the Gulf appear to form a large, genetically isolated population with relatively low genetic diversity. C_LIO_LIThis is the first study that evaluates population structure and genetic diversity of this endangered seabird. C_LIO_LIThis is important information for the conservation of the Gulf Socotra cormorants because low genetic diversity, coupled with relative isolation, is associated with reduced fitness, and suggests that they may have a lower chance to adapt to environmental changes. C_LI

ecology↗