Calcium channel blockers are widely used to treat hypertension by reducing vascular contraction. However, numerous animal experiments and clinical trials failed to demonstrate a beneficial effect on outcome of using calcium channel blockers to treat stroke (1,2). Severe side effect of systemic hypotension often occurred during treatment. Voltage-gated Cav1.2 channels are expressed in cardiovascular system and are the main targets for calcium blocker, dihydropyridine. The aim of the study was to investigate the molecular and functional changes of Cav1.2 channels in cerebral vascular smooth muscle cells under hypoxia conditions. Both primary cultured cerebral vascular smooth muscle cells from Wistar rats and A7r5 cell line were used for the study. After chronic hypoxia and glucose deprivation treatment for one day or three days, Cav1.2 channel expression was reduced gradually in both types of cells. Increase of intracelluar calcium concentration in response to membrane depolarization by application of 145 mM K+ into the bath solution was reduced in hypoxic cells as compared with normoxic cells. Interestingly, hypoxic cells also exhibited enhanced sensitivity to calcium channel blocker isradipine (10nM in A7r5 cells and 5nM in primary cultured cells). After scanning the transcript of Cav1.2 channels, we identified the expression of two alternatively spliced exons were altered both in A7r5 cells and primary cultured cells. More Exon 33 was deleted and exon 9* included after chronic hypoxia treatment. Such changes could lead to more dihydropiridine sensitivity and a similar trend was identified in rat hearts of myocardial infarction with altered electrophysiological properties in our previous reports (3,4). We thus postulate that the splicing profile changes of Cav1.2 channels could contribute at least partially to the altered dihydrapiridine sensitivities after hypoxia. These isoforms of Cav1.2 channels are a novel target for designing therapeutic drugs targeting cerebral blood vessels after stroke with minimal side effect on systemic blood vessels. 1) Horn J, de Haan RJ, Vermeulen M, Luiten PG, Limburg M. Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke. 2001, 32(10):2433-8. 2) Infeld B, Davis SM, Donnan GA, Yasaka M, Lichtenstein M, Mitchell PJ, Fitt GJ. Nimodipine and perfusion changes after stroke. Stroke. 1999, 30(7):1417-23 3) Liao P, Li G, Yu de J, Yong TF, Wang JJ, Wang J, Soong TW. Molecular alteration of Ca(v)1.2 calcium channel in chronic myocardial infarction. Pflugers Arch. 2009, 458(4):701-11. 4) Liao P, Yu D, Li G, Yong TF, Soon JL, Chua YL, Soong TW. A smooth muscle Cav1.2 calcium channel splice variant underlies hyperpolarized window current and enhanced state-dependent inhibition by nifedipine. J Biol Chem. 2007, 30;282(48):35133-42.