Maladaptive response of arterial myocytes to chronic exposure to Ca2+ channel blockers.

> “The tragedies in life are largely arterial.” > > – Sir William Osler, 1908 (1) Hypertension is a debilitating cardiovascular disease characterized by the narrowing of arteries and arterioles which increases resistance to blood flow. This decrease in intraluminal diameter of arteries/arterioles is due to multiple factors, including arterial smooth muscle hypertrophy and hyperplasia as well as increased myogenic tone. Up-regulation of L-type Ca2+ channel activity is a major contributor to enhanced arterial smooth muscle contractility during hypertension (2, 3). Accordingly, current pharmacological guidelines for the treatment of hypertension include the use of L-type Ca2+ channel blockers such as nifedipine or amlodipine (4). In PNAS, Johnson et al. (5) report that chronic exposure to a broad range of these drugs promotes arterial smooth muscle to transition from a contractile to a proliferative phenotype by activating stromal-interacting molecule (STIM)/ORAI store-operated Ca2+ entry (SOCE) (Fig. 1). These findings have profound implications for our understanding of how L-type Ca2+ channel blockers affect vascular function during hypertension and may lead to changes on treatment of the pathology. Fig. 1. Response of contractile and synthetic smooth muscle to hypertension and L-type Ca2+ blockers. ( A ) During hypertension, contractile myocytes shorten in response to increased CaV1.2 channel activity, whereas synthetic myocytes experience a reduction in contractile proteins and increase in SOCE machinery. L-type Ca2+ blockers elicit a decrease in CaV1.2 influx, promoting relaxation and vasodilation. Synthetic myocytes see an increase in SOCE, proliferation, and migration, resulting in hyperplasia and increased incidence of heart failure. ( B ) L-type Ca2+ channel blockers stimulate the assembly of the STIM1/ORAI complexes via an unknown mechanism. The STIM1/ORAI complex promotes SOCE independent of S/ER Ca2+ content or CaV1.2 function. SOCE increases [Ca2+]i and promotes proliferation and migration of … [↵][1]1To whom correspondence may be addressed. Email: lfsantana{at}ucdavis.edu. [1]: #xref-corresp-1-1