Better understanding of phosphoinositide 3-Kinase (PI3K) pathways in vasculature: towards precision therapy targeting angiogenesis and tumor blood supply

Item Type:	Article
Title:	Better understanding of phosphoinositide 3-Kinase (PI3K) pathways in vasculature: towards precision therapy targeting angiogenesis and tumor blood supply
Creators Name:	Tsvetkov, D. and Shymanets, A. and Huang, Y. and Bucher, K. and Piekorz, R. and Hirsch, E. and Beer-Hammer, S. and Harteneck, C. and Gollasch, M. and Nürnberg, B.
Abstract:	The intracellular PI3K-AKT-mTOR pathway is involved in regulation of numerous important cell processes including cell growth, differentiation, and metabolism. The PI3K{alpha} 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 PI3K{alpha} and other class I isoforms, i.e. PI3K{beta}, {gamma}, {delta}, 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 PI3K{gamma} and PI3K{delta} (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 {my}M). These vasoconstrictions were also inhibited by the PI3K{alpha} isoform inhibitors A66 (10 {my}M) and PI-103 (1 {my}M), but not by the PI3K{beta} isoform inhibitor TGX 221 (100 nM). Pik3cg(-/-)/Pik3cd(-/-)-arteries showed normal vasoconstriction. We conclude that PI3K{alpha} is an important downstream element in vasoconstrictor GPCR signaling, which contributes to arterial vasocontraction via {alpha}1-adrenergic receptors. Our results highlight a regulatory role of PI3K{alpha} in the cardiovascular system, which widens the spectrum of gene therapy approaches targeting PI3K{alpha} in cancer cells and tumor angiogenesis and regional blood flow.
Keywords:	p110{alpha}, Phenylephrine, {alpha}1-adrenergic receptor, PI3K/Akt, Animals, Mice
Source:	Biochemistry
ISSN:	0006-2979
Publisher:	MAIK Nauka/Interperiodica
Volume:	81
Number:	7
Page Range:	691-699
Date:	July 2016
Additional Information:	Published in Russian in: Biokhimiya 81(7):915-925.
Official Publication:	https://doi.org/10.1134/S0006297916070051
PubMed:	View item in PubMed

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