Better Understanding of Phosphoinositide 3-Kinase (PI3K) Pathways in Vasculature: Towards Precision Therapy Targeting Angiogenesis and Tumor Blood Supply

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D. Tsvetkov^1#, A. Shymanets^2#, Yu Huang³, K. Bucher², R. Piekorz⁴, E. Hirsch⁵, S. Beer-Hammer², C. Harteneck^2&, M. Gollasch^1*, and B. Nürnberg^2*

¹Charité University Medicine Berlin, Experimental and Clinical Research Center, Section Nephrology/Intensive Care, 13125 Berlin, Germany; E-mail: maik.gollasch@charite.de

²Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Pharmacology and Experimental Therapy, 72074 Tübingen, Germany; E-mail: bernd.nuernberg@uni-tuebingen.de

³Chinese University of Hong Kong, School of Biomedical Sciences, 223A, Lo Kwee-Seong Integrated Biomedical Sciences Building, Area 39, Hong Kong, China

⁴Heinrich Heine University Düsseldorf, Institute for Biochemistry and Molecular Biology II, 40225 Düsseldorf, Germany

⁵University of Torino, Molecular Biotechnology Centre, Department of Molecular Biotechnology and Health Sciences, 10126 Turin, Italy

^# These authors contributed equally to this work.

^& Deceased.

^* To whom correspondence should be addressed.

Received February 26, 2016; Revision received April 12, 2016

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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.

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KEY WORDS: p110α, phenylephrine, α₁-adrenergic receptor, PI3K/Akt

DOI: 10.1134/S0006297916070051

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