Hypoxic remodelling of Ca(2+) signalling in proliferating human arterial smooth muscle.
Ca(2+) homeostasis in proliferating smooth muscle (SM) cells strongly influences neointima formation, which can cause failure of coronary artery bypass surgery. During surgical procedures and subsequent revascularization, SM cells are also exposed to a period of hypoxia. Problems with bypass surgery in general involve neointima formation which is in turn dependent on SM proliferation and migration. Here, we have directly monitored [Ca(2+)](i) fluorimetrically in proliferating internal mammary artery (IMA) SM cells, and investigated how this is modulated by chronic hypoxia (CH; 24 h, 2.5% O(2)). IMA is the most successful replacement conduit vessel in bypass grafts. Basal [Ca(2+)](i) was unaffected by CH, but removal of extracellular Ca(2+) evoked far smaller reductions in [Ca(2+)](i) than were seen in normoxic cells. Voltage-gated Ca(2+) entry was suppressed in CH cells, and this was attributable to activation of the transcriptional regulator, hypoxia inducible factor. Furthermore, the relative contributions to voltage-gated Ca(2+) entry of L- and T-type Ca(2+) channels was markedly altered, with T-type channels becoming functionally more important in CH cells. Agonist-evoked mobilization of Ca(2+) from intracellular stores was not affected by CH, whilst subsequent capacitative Ca(2+) entry was modestly suppressed. Our data provide novel observations of the remodelling of Ca(2+) homeostasis by CH in IMASM cells which may contribute to their superior patency as coronary bypass grafts.
Aley
Parvinder K
PK
Division of Cardiovascular and Neuronal Remodelling, Leeds Institute of Genetics, Health & Therapeutics, University of Leeds, Level 10, Worsley Building, Leeds, LS2 9JT, UK.
Wilkinson
Jenny A
JA
Bauer
Claudia C
CC
Boyle
John P
JP
Porter
Karen E
KE
Peers
Chris
C
D001158:Arteries / Q000166:cytology*; D001920:Bradykinin / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology
D015220:Calcium Channels; D051793:Hypoxia-Inducible Factor 1; D011188:Potassium; D001920:Bradykinin