Soluble guanylate cyclase (sGC) down-regulation by abnormal extracellular matrix proteins as a novel mechanism in vascular dysfunction: Implications in metabolic syndrome.

at Penylvania State U niersity on Feruary 3, 2013 scres.oxjournals.org/ Vascular dysfunction plays a role in most if not all cardiovascular disorders. Vascular dysfunction is defined as impaired vasodilation in response to agonists such as acetylcholine (ACh) that mediate vascular smooth muscle relaxation through release of the endothelial derived relaxing factor (EDRF) nitric oxide (NO). There is a wealth of literature to support the understanding that endothelial dysfunction is due to a decreased NO synthesis or an increased NO inactivation. Endothelial dysfunction is generally thought to be responsible for vascular dysfunction, and the terms are often used interchangeably. But the mechanism(s) responsible for vascular dysfunction is (are) far from being completely understood, and labeling all vascular dysfunction as endothelial dysfunction may be application of a misnomer in some cases. Alterations in the cell signaling cascade downstream of NO production and release could explain vascular dysfunction in certain conditions. Nowadays, it is textbook information that NO induces cell relaxation by interacting with sGC and causing an increase in cyclic guanosine monophosphate (cGMP). The end result is thought to be a decrease in intracellular cytoplasmic calcium due to decreased intracellular calcium release [1] and/or increased cGMP-dependent calcium pump activity [1] and/or due to decreased calcium influx because of the opening of K channels, resulting in hyperpolarization and the consequent closing of L-type Ca channels [1,2]. So, could vascular dysfunction be explained by alterations in the target tissue response to NO? In particular, could alterations in smooth muscle sGC or cGMP or vasodilator-stimulated