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(Circulation. 2005;112:1628-1635.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Regression of Medial Elastocalcinosis in Rat Aorta

A New Vascular Function for Carbonic Anhydrase

Rachida Essalihi, MSc; Huy Hao Dao, PhD; Liz-Ann Gilbert, MSc; Céline Bouvet, MSc; Yves Semerjian, BPharm; Marc D. McKee, PhD; Pierre Moreau, PhD

From the Faculty of Pharmacy, Université de Montréal (R.E., H.H.D., L.G., C.B., Y.S., P.M.); and Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University (M.D.M.), Montréal, Québec, Canada.

Correspondence to Pierre Moreau, PhD, Faculty of Pharmacy, Université de Montréal, 2900 Édouard-Montpetit, Pavillon Jean-Coutu, Rm 3197, PO Box 6128, Stn Centre-Ville, Montréal, Québec, H3C 3J7 Canada. E-mail pierre.moreau{at}umontreal.ca

Received December 14, 2004; revision received June 7, 2005; accepted June 9, 2005.

Background— We sought to determine whether carbonic anhydrase (CA), which plays an important role in bone resorption, contributes to vascular mineral loss induced by an endothelin receptor antagonist.

Methods and Results— Wistar rats were compared with rats receiving warfarin and vitamin K₁ (WVK) for 8 weeks alone or in association with the endothelin receptor antagonist darusentan (30 mg/kg per day), the CA inhibitor acetazolamide (100 mg/kg per day), or both for the last 4 weeks. Rats were also treated with WVK for 5 or 6 weeks, and darusentan was added for the last week or last 2 weeks of treatment, respectively. Treatment with WVK produced medial elastocalcinosis in the aorta and carotid arteries. Immunohistochemistry revealed that CA II was already abundant in the adventitia and in calcified areas of aortic sections from WVK-treated rats. Darusentan did not significantly modify its abundance or distribution. In contrast, CA IV immunostaining, which was weak in WVK-treated rats, became apparent after 1 week of darusentan treatment and declined toward basal levels thereafter. These findings were confirmed by a parallel increase in CA IV protein abundance and activity in the aorta. The mineral loss induced by darusentan was blunted by acetazolamide treatment, confirming the functional relevance of the biochemical findings. Moreover, CA IV immunostaining was enhanced much later in the carotids, where darusentan did not cause regression of elastocalcinosis.

Conclusions— Vascular mineral loss induced by the blockade of endothelin receptors seems dependent on the activation of membrane-bound CA IV, suggesting that mineral loss may proceed via local changes in pH similar to that seen in bone resorption.

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