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Monitoring Functionality and Morphology of Vasculature Recruited by Factors Secreted by Fast-growing Tumor-generating Cells
Published on: November 23, 2014
Better Understanding of Phosphoinositide 3-Kinase (PI3K) Pathways in Vasculature: Towards Precision Therapy Targeting
D Tsvetkov1, A Shymanets, Yu Huang
1Charité University Medicine Berlin, Experimental and Clinical Research Center, Section Nephrology/Intensive Care, Berlin, 13125, Germany. maik.gollasch@charite.de.
Abstract:
The intracellular PI3K-AKT-mTOR pathway is involved in regulation of numerous important cell processes including cell growth, differentiation, and metabolism. The PI3Kα isoform has received particular attention as a novel molecular target in gene therapy, since this isoform plays critical roles in tumor progression and tumor blood flow and angiogenesis. However, the role of PI3Kα and other class I isoforms, i.e. PI3Kβ, γ, δ, in the regulation of vascular tone and regional blood flow are largely unknown. We used novel isoform-specific PI3K inhibitors and mice deficient in both PI3Kγ and PI3Kδ (Pik3cg(-/-)/Pik3cd(-/-)) to define the putative contribution of PI3K isoform(s) to arterial vasoconstriction. Wire myography was used to measure isometric contractions of isolated murine mesenteric arterial rings. Phenylephrine-dependent contractions were inhibited by the pan PI3K inhibitors wortmannin (100 nM) and LY294002 (10 µM). These vasoconstrictions were also inhibited by the PI3Kα isoform inhibitors A66 (10 µM) and PI-103 (1 µM), but not by the PI3Kβ isoform inhibitor TGX 221 (100 nM). Pik3cg(-/-)/Pik3cd(-/-)-arteries showed normal vasoconstriction. We conclude that PI3Kα is an important downstream element in vasoconstrictor GPCR signaling, which contributes to arterial vasocontraction via α1-adrenergic receptors. Our results highlight a regulatory role of PI3Kα in the cardiovascular system, which widens the spectrum of gene therapy approaches targeting PI3Kα in cancer cells and tumor angiogenesis and regional blood flow.
Insights
Phosphoinositide 3-kinase alpha (PI3Kα) regulates arterial vasoconstriction. Inhibiting PI3Kα reduces blood vessel contraction, highlighting its cardiovascular role and potential therapeutic applications.
Area of Science:
- Molecular Biology
- Cardiovascular Physiology
- Pharmacology
Background:
- The PI3K-AKT-mTOR pathway regulates critical cellular functions like growth and metabolism.
- PI3Kα is a key target in gene therapy for cancer due to its role in tumor progression and angiogenesis.
- The function of PI3K isoforms in vascular tone and blood flow regulation remains largely unexplored.
Purpose of the Study:
- To investigate the contribution of PI3K isoforms to arterial vasoconstriction.
- To determine the specific role of PI3Kα in regulating vascular tone.
Main Methods:
- Utilized isoform-specific PI3K inhibitors and PI3Kγ/δ deficient mice.
- Employed wire myography to assess isometric contractions in isolated murine mesenteric arterial rings.
- Measured phenylephrine-induced vasoconstriction responses.
Main Results:
- Pan PI3K inhibitors (wortmannin, LY294002) significantly inhibited phenylephrine-dependent vasoconstriction.
- PI3Kα-specific inhibitors (A66, PI-103) also reduced vasoconstriction, while PI3Kβ inhibitor (TGX 221) had no effect.
- Arteries from PI3Kγ/δ deficient mice exhibited normal vasoconstriction, indicating these isoforms are not critical for this process.
Conclusions:
- PI3Kα is a crucial downstream mediator in G-protein coupled receptor (GPCR) signaling, contributing to arterial vasoconstriction via α1-adrenergic receptors.
- PI3Kα plays a significant regulatory role in the cardiovascular system.
- These findings expand therapeutic strategies targeting PI3Kα beyond cancer, including its potential in managing tumor angiogenesis and regional blood flow.
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