Some of the molecules present in different cerebral vascular segments that are involved in vascular dysfunction during I/R and may be important targets for vascular protection. At the level of MCA, I/R affect endothelial cells through an increase in [Ca2+]i. High calcium levels alter activity of enzymes such as eNOS which produces potentially toxic amounts of NO. The excess of NO combines with others RONS such as O2- to form ONOO-, which decreases the effectiveness of NO and interacts with lipids, DNA and proteins causing cell dysfunction and death. eNOS activity is also affected by limited availability and oxidation of the cofactor BH4 and by changes in its phosphorylation state. In addition, extracellular hyperglycemia activates Glut-1 transporters, causing endothelial intracellular hyperglycemia which induces a variety of detrimental changes in vascular cerebral cells. In contrast, activation of ETB receptor by an increase in ET-1 production during I/R may have a protective role in cerebral ischemic injury. In VSM, I/R cause increased RONS that damages important structures, including the actin cytoskeleton. ONOO- causes nitrosylation of F-actin and loss of myogenic tone. This pathological mechanism is fed by increased expression of iNOS that produces large amounts of NO for long periods and by ETA receptors activation that increases oxidative stress. At the level of penetrating arterioles the signaling molecules that play an important role in vascular function are eNOS, iNOS, EDHF and SK and IK channels. Penetrating arterioles have considerable basal tone despite I/R and this likely contributed to expansion of the infarct into the penumbra. Thus, remodeling of penetrating arterioles to increase lumen diameter may also be highly protective of the penumbra. Finally, postischemic inflammatory processes and RONS production, that are enhanced by iNOS activity, can also compromise the microcirculation. These effects on the microcirculation can significantly exacerbate damage to the ischemic penumbra. An important mediator of stroke outcome is the nonselective cation channel NCCa-ATP which is involved in cytotoxic edema. In addition, expression and activation of MMPs, ETA receptors and PKC can cause BBB disruption and hemorrhagic transformation. (Abbreviations: [Ca2+]i: intracellular calcium; eNOS: endothelial nitric oxide synthase; RONS: reactive oxygen and nitrogen species; O2-: superoxide; ONOO-: peroxynitrite; BH4: tetrahydrobiopterin; Glut-1: glucose transporter 1; ETB receptor: endothelin-1 receptor type B; VSM: vascular smooth muscle; iNOS: inducible nitric oxide synthase; ETA receptor: endothelin-1 receptor type A; EDHF: endothelium-derived hyperpolarizing factor; SK: small-conductance calcium-activated potassium channel; IK: intermediate- conductance calcium-activated potassium channel; NCCa-ATP: nonselective cation channel regulated by cytoplasmic Ca2+ and ATP; MMPs: matrix metalloproteinases; and PKC: protein kinase C).
