Shear stress and pathophysiological PI3K involvement in vascular malformations

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(10)

Опубликована: Май 14, 2024

Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain-of-function (GOF) mutations in the gene encoding catalytic α subunit PI3Kα (PIK3CA). These PIK3CA are known to cause solid cancers when occurring other tissues. PIK3CA-related anomalies, or "PIKopathies," range from simple, i.e., restricted a particular form malformation, complex, presenting with hyperplasia phenotypes, including overgrowth spectrum. Interestingly, development PIKopathies is by fluid shear stress (FSS), physiological stimulus caused blood lymph flow. findings implicate PI3K mediating EC responses FSS conditions characteristic lymphatic and capillary vessel beds. Consistent this hypothesis, increased signaling also contributes cerebral cavernous malformations, disorder affects low-perfused brain venous capillaries. Because GOF activity its partners excellent drug targets, understanding PIK3CA's role may inform therapeutic strategies normalize diseased state. This Review focuses on discusses current dysregulation particularly affect regions vasculature. We discuss recent surprising linking fast-flow arteriovenous malformations hereditary hemorrhagic telangiectasias.

Язык: Английский

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Discovery of Novel PI3KC2γ Inhibitors with High Potency, Selectivity, and Favorable Pharmacokinetics for Glycogen Metabolism Regulation

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117621 - 117621

Опубликована: Апрель 1, 2025

Язык: Английский

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PI3K Signaling at the Crossroads of Lipid Metabolism and Cancer

Advances in experimental medicine and biology, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Язык: Английский

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