Brain-derived neurotrophic factor stimulates production of prostacyclin in cerebral arteries.
OBJECTIVE
The role of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B, in control of cerebral circulation is poorly understood. The present study was designed to investigate the cerebral vascular effects of BDNF in vivo.


METHODS
Replication incompetent adenovirus encoding either rat BDNF (AdBDNF) or green fluorescent protein was injected intracisternally into rabbits. Forty-eight hours later, animals were euthanized. Plasma and cerebrospinal fluid levels of BDNF were measured by enzyme-linked immunosorbent assay, vasomotor function of isolated basilar arteries was studied in organ chambers, protein expression in the basilar arteries was studied by Western blotting, prostanoid levels were measured by enzyme-linked immunosorbent assay, and cyclic adenosine 3',5'-monophosphate levels were measured by radioimmunoassay.


RESULTS
The levels of BDNF in the cerebrospinal fluid were significantly elevated in AdBDNF-treated rabbits as compared with adenovirus encoding green fluorescent protein-treated rabbits (37+/-5 ng/mL versus 0.006+/-0.003 ng/mL, respectively; P<0.05; n=14). Western blotting studies revealed that in basilar arteries, AdBDNF increased protein expression of prostacyclin synthase, whereas expression of endothelial nitric oxide synthase and phosphorylated (Ser 1177) endothelial nitric oxide synthase remained unchanged. During incubation with arachidonic acid (1 micromol/L), PGI(2) production and levels of cyclic adenosine 3',5'-monophosphate were significantly elevated only in AdBDNF-treated rabbit basilar arteries (P<0.05, n=6). Relaxations to acetylcholine (10(-9) to 10(-5) mol/L) and arachidonic acid (10(-9) to 10(-5) mol/L) were significantly potentiated in basilar arteries from rabbits injected with AdBDNF. Potentiation of relaxations to acetylcholine in AdBDNF-treated basilar arteries was inhibited by the nonselective cyclooxygenase inhibitor, indomethacin (10(-5) mol/L, P<0.05, n=6) and constitutive phospholipase A(2) inhibitor, AACOCF3 (2x10(-5) mol/L, P<0.05, n=5).


CONCLUSIONS
Our results demonstrate that in cerebral arteries, BDNF-induced activation of tropomyosin receptor kinase B receptor signaling in vivo promotes prostacyclin biosynthesis. These findings provide novel mechanistic insight into the vascular protective effect of BDNF in cerebral circulation.
Santhanam
Anantha Vijay R
AV
Departments of Anesthesiology, and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.
Smith
Leslie A
LA
Katusic
Zvonimir S
ZS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001488:Basilar Artery / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood / Q000134:cerebrospinal fluid* / Q000235:genetics; D002536:Cerebral Arteries / Q000378:metabolism*; D002556:Cerebrospinal Fluid Proteins / Q000032:analysis / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000096:biosynthesis*; D005822:Genetic Vectors; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011817:Rabbits; D020813:Receptor, trkB / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics; D014664:Vasodilation / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D002556:Cerebrospinal Fluid Proteins; D016861:Cyclooxygenase Inhibitors; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D000242:Cyclic AMP; D020813:Receptor, trkB; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase