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Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-driven refractory vascular malformations

ABSTRACT: Congenital vascular malformations, affecting 0.5% of the population, frequently occur in the head and neck, complicating treatment due to their vital functions. Our previous research identified distinct developmental origins for blood and lymphatic vessels in these regions in both mouse and human embryos. In this study, we expressed Pik3caH1047R in the cardiopharyngeal mesoderm (CPM) to investigate the pathogenesis of these malformations. Mice expressing Pik3caH1047R in the CPM developed abnormal vasculature restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3caH1047R promotes Vegf-a expression in endothelial cells via Hif-driven hypoxia signaling. Human samples corroborated these findings, showing elevated HIF-1α and VEGF-A in malformed vessels. Notably, treatment with Hif-1α and Vegf-a inhibitors significantly reduced abnormal vasculature in the mouse model. Our findings highlight the role of developmental origins and hypoxia-driven mechanisms in vascular malformations, providing a basis for developing targeted therapies for these refractory conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE279129 | GEO | 2025/03/12

REPOSITORIES: GEO

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Project description:Bacterial meningitis is a deadly disease most commonly caused by Streptococcus pneumoniae that leads to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer of S. pneumoniae from hematogenous source into the brain across the blood-brain barrier (BBB); the mechanisms however are still poorly understood. Current treatment strategies include adjuvant dexamethasone therapy for cerebral edema, the prime reason for neurological complications and mortality, which is followed up by antibiotics. The success of corticosteroids is however inconclusive, necessitating the development of new therapies for controlling cerebral edema. We have previously shown a general activation of hypoxia inducible factor (HIF-1α) in bacterial infections, we therefore hypothesized that HIF-1α, via induction of vascular endothelial growth factor (VEGF) is critically involved in the transmigration of pathogens across the BBB. In human and murine meningitis brain samples, HIF-1 activation was observed by immunohistochemistry. HIF-1α/VEGF expression and permeability was therefore analyzed in vitro in infected brain endothelial cells (ECs). Localization of S. pneumoniae in brain ECs from mouse/human sources was visualized in vitro and in vivo by confocal, super-resolution, and electron microscopy. S. pneumoniae infection in brain ECs resulted in upregulation of HIF-1α/VEGF by Western blotting and qRT-PCR that was associated with increased paracellular permeability, which was supported by bacterial localization at cell-cell junctions. RNA sequencing of brain microvessels from hematogenously infected mice with increased permeability and S. pneumoniae deposition in the brain showed upregulation of genes in HIF-1α/VEGF pathway. Inhibition of HIF-1α with echinomycin, siRNA in bEnd5 cells and by using primary brain ECs from HIF-1α KO mice revealed a reduced endothelial permeability and transmigration of S. pneumoniae. We thus demonstrate a critical role for HIF-1α/VEGF in transmigration of S. pneumoniae across the BBB and propose targeting this pathway to prevent BBB dysfunction in infections.

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Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-driven refractory vascular malformations

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