Differential regulation of vascular tone and remodeling via stimulation of type 2 and type 6 adenylyl cyclases in the ductus arteriosus.
BACKGROUND
Prostaglandin (PG)E(2), which increases intracellular cAMP via activation of adenylyl cyclases (ACs), induces vasodilation and hyaluronan-mediated intimal thickening (IT) in the ductus arteriosus (DA) during late gestation. After birth, however, differential regulation of vasodilation and IT is preferable for treatment of patients with patent DA and DA-dependent congenital cardiac malformations.


OBJECTIVE
Our objectives were to examine whether AC isoforms play differential roles in DA vasodilation and IT.


RESULTS
AC2 and AC6 were more highly expressed in rat DA than in the aorta during the perinatal period. AC6-targeted siRNA counteracted PGE(1)-induced hyaluronan production in rat DA smooth muscle cells. Overexpression of AC6 enhanced PGE(1)-induced hyaluronan production and induced IT in DA explants. Furthermore, IT of the DA was less marked in mice lacking AC6 than in wild-type and AC5-deficient mice. Stimulation of AC2 attenuated AC6-induced hyaluronan production via inhibition of the p38 mitogen-activated protein kinase pathway and AC6-induced IT of the DA. An AC2/6 activator, 6-[N-(2-isothiocyanatoethyl) aminocarbonyl] forskolin (FD1), did not induce hyaluronan-mediated IT in DA explants, although an AC5/6 activator, 6-[3-(dimethylamino)propionyl]-14,15-dihydroforskolin (FD6) did. Moreover, FD1 induced longer vasodilation of the DA than did PGE(1) without significant adverse effects in vivo.


CONCLUSIONS
AC6 is responsible for hyaluronan-mediated IT of the DA and AC2 inhibited AC6-induced hyaluronan production. Stimulation of both AC2 and AC6 by FD1 induced longer vasodilation without hyaluronan-mediated IT in the DA in vivo. FD1 may be a novel alternative therapy to currently available PGE therapy for patients with DA-dependent congenital heart disease.
Yokoyama
Utako
U
Department of Life Science and Medical Bioscience, Waseda University Graduate School of Advanced Science and Engineering, 2-2, Wakamatsu-cho, TWIns, Shinjuku-ku, Tokyo 162-8480, Japan.
Minamisawa
Susumu
S
Katayama
Ayako
A
Tang
Tong
T
Suzuki
Sayaka
S
Iwatsubo
Kousaku
K
Iwasaki
Shiho
S
Kurotani
Reiko
R
Okumura
Satoshi
S
Sato
Motohiko
M
Yokota
Shumpei
S
Hammond
H Kirk
HK
Ishikawa
Yoshihiro
Y
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004373:Ductus Arteriosus / Q000166:cytology / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D017539:Tunica Intima / Q000502:physiology; D014664:Vasodilation / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007527:Isoenzymes; D005576:Colforsin; D006820:Hyaluronic Acid; D000242:Cyclic AMP; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D000262:Adenylyl Cyclases; C100622:adenylyl cyclase 2; C121100:adenylyl cyclase 6; C419510:adenylyl cyclase type V