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Role of PI 3-kinase isoform p110α for vascular integrity and aortic aneurysm formation

The pathobiology of vascular diseases like aortic aneurysms involves distinct cell types of the aortic wall and is characterized by vascular inflammation, extracellular matrix degeneration, and, in particular, by loss and dedifferentiation of vascular smooth muscle cells (SMCs). In mature blood vessels, the integrity of the vessel wall is maintained by a balanced homeostasis between low-grade mitogenic and anti-apoptotic/necroptotic signals, which are mainly mediated by receptor tyrosine kinase (RTK)-dependent activation of phosphatidylinositol 3’-kinase (PI3K). RTKs activate class IA PI3K isoforms, which are characterized by one of three catalytic p110 subunits. In SMCs, the p110α subunit mediates RTK-dependent proliferation, chemotaxis, and survival. Moreover, SMCs from smooth muscle specific p110α-deficient mice (SM-p110α-/-) have largely lost their plasticity. SM-p110α-/- mice display reduced medial wall thickness, substantially reduced neointima formation and media hypertrophy after balloon injury of the carotid artery, and protection from experimental pulmonary hypertension. Detailed analysis of the aortic wall in SM-p110α-/- mice uncovers a disturbed structure of the media and increased vascular inflammation. Furthermore, preliminary data indicate that p110α deficiency in SMCs promotes abdominal aortic aneurysm (AAA) formation in mice. These data suggest a significant role of p110α for vascular integrity and thus for the pathobiology of aortic aneurysms.

We hypothesize that loss of p110α signaling impairs vascular integrity and promotes development and progression of aortic aneurysms.

We plan to elucidate how p110α signaling can affect aortic aneurysm formation, SMC phenotypic modulation, extracellular matrix homoeostasis, and vascular inflammation. In Aim 1, we will address the specific role of p110α signaling in the development and progression of abdominal and thoracic aortic aneurysms in mice and humans. Aim 2 focuses on the effects of p110α deficiency on SMC phenotypic modulation (synthetic versus contractile), whereas Aim 3 concentrates on the impact of p110α on expression and structure of extracellular matrix (ECM) components and elastic fibers. Finally, Aim 4 addresses the impact of p110αdeficiency in SMCs on vascular inflammation, EC function, and cell death.
Since recently developed selective p110α inhibitors are currently being tested in clinical trials for the treatment of various malignant diseases, characterization of the importance of p110α for the pathobiology of AAAs is of the utmost relevance, in order to avoid exposition of individuals with a predisposition to AAAs to p110α inhibition, but also to identify a targetable mediator as a novel strategy for the treatment and prevention of AAA formation.




B06 Hypothesis: p110α signaling is integral to maintaining vascular integrity and disruption of this pathway leads to the development and progression of aortic aneurysms.

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