Using an integrative approach and a newly developed mouse model expressing a Ca2+ biosensor exclusively in endothelial cells, we elucidated the underlying molecular mechanisms responsible for activation of TRPA1 channels in the intact cerebral endothelium during hypoxia and investigated the pathophysiological impact of this novel pathway in vivo using an established model of ischemic strokes. The gene discussed is TRPA1; the disease is ischemic stroke.