AAV transduction of the MaxiK channel gene in vascular smooth muscle cells for the long‐term control of hypertension

Abstract

The hallmark finding in chronic hypertension is the presence of anomalous vascular tone. We propose a novel therapeutic approach of adeno-associated-virus (AAV) transduction of a dilator K+ channel gene into resistance arteries for the long-term control of hypertension. We have chosen the high-conductance, Ca2+-activated potassium (MaxiK) channel as the logical transgene, since it opens during arterial activation as a negative feedback mechanism to normalize vascular tone. Thus, we hypothesize that AAV delivery of pore-forming, MaxiK α-subunits into the vascular smooth muscle cells (VSMCs) of resistance arteries will reduce blood pressure in hypertensive mice, but not profoundly affect resting blood pressure levels. We have constructed the AAV vector with the mouse MaxiK transgene (mSlo) using two smooth muscle specific promoters, including a truncated form of the SM22α promoter that shows VSMC specificity (J. Cell Biol. 132:, 1996). Also, we have constructed an AAV vector using a newly designed “MusPrB” promoter derived from the cardiac myosin heavy chain promoter that prefers VSMC transgene expression. Before injecting the viral constructs into mice to evaluate their anti-hypertensive effect, the specificity and efficacy of the SM22α and MusPrB promoters are being compared between different cell types, and the properties of the mSlo transgene product are being analyzed. (NIH R01 HL59238-08)