ClC-3: more than just a volume-sensitive Cl- channel.

Pulmonary vascular medial hypertrophy due to enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and/or decreased PASMC apoptosis is a primary cause of increased pulmonary vascular resistance and arterial pressure in patients with pulmonary arterial hypertension. While many factors can contribute to this form of vascular remodeling, it is generally agreed upon that altered transmembrane ion flux via ion channels is involved. While much focus has centered on the role of cations and cation channels in controlling PASMC contraction and proliferation, anion efflux via Cl- channels has recently gained interest for its role in SMC proliferation, differentiation, migration, contraction, and angiogenesis. In this issue, Dai et al. report that the putative volume-sensitive ClC-3 channel is upregulated in PASMC from monocrotaline-induced pulmonary hypertensive rats and in inflammatory cytokine-treated canine PASMC. They also provide evidence that ClC-3 upregulation may protect against oxidative stress-induced PASMC necrosis, thereby improving PASMC survival and promoting medial hypertrophy.