A novel regulator of angiogenesis in endothelial cells: 5-hydroxytriptamine 4 receptor.
The 5-hydroxytryptamine type 4 receptor (5-HT(4)R) regulates many physiological processes, including learning and memory, cognition, and gastrointestinal motility. Little is known about its role in angiogenesis. Using mouse hindlimb ischemia model of angiogenesis, we observed a significant reduction of limb blood flow recovery 14 days after ischemia and a decrease in density of CD31-positive vessels in adductor muscles in 5-HT(4)R(-/-) mice compared to wild type littermates. Our in vitro data indicated that 5-HT(4)R endogenously expressed in endothelial cells (ECs) may promote angiogenesis. Inhibition of the receptor with 5-HT(4)R antagonist RS 39604 reduced EC capillary tube formation in the reconstituted basement membrane. Using Boyden chamber migration assay and wound healing "scratch" assay, we demonstrated that RS 39604 treatment significantly suppressed EC migration. Transendothelial resistance measurement and immunofluorescence analysis showed that a 5-HT(4)R agonist RS 67333 led to an increase in endothelial permeability, actin stress fiber and interendothelial gap formation. Importantly, we provided the evidence that 5-HT(4)R-regulated EC migration may be mediated by Gα13 and RhoA. Our results suggest a prominent role of 5-HT(4)R in promoting angiogenesis and identify 5-HT(4)R as a potential therapeutic target for modulating angiogenesis under pathological conditions.
Department of Pharmacology, College of Medicine, University of Illinois, Chicago, USA. Jasmina.Profirovic@stlcop.edu
Jasmina
J
Profirovic
Elena
E
Strekalova
Norifumi
N
Urao
Aleksandar
A
Krbanjevic
Alexandra V
AV
Andreeva
Sudhahar
S
Varadarajan
Tohru
T
Fukai
René
R
Hen
Masuko
M
Ushio-Fukai
Tatyana A
TA
Voyno-Yasenetskaya
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D002448:Cell Adhesion / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009132:Muscles / Q000098:blood supply / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology; D058832:Serotonin 5-HT4 Receptor Antagonists / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000814:Aniline Compounds; D010880:Piperidines; C475107:RS 39604; D058828:Serotonin 5-HT4 Receptor Agonists; D058832:Serotonin 5-HT4 Receptor Antagonists; D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333; D017868:Cyclic AMP-Dependent Protein Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020742:rhoA GTP-Binding Protein; D011407:Propane