Haptoglobin Restores Nitric Oxide-Mediated Vasodilation in Hemoglobin-Exposed Porcine Basilar Arteries Ex Vivo

Aneurysmatic subarachnoid hemorrhage leads to a massive release of hemoglobin from lysing erythrocytes into the cerebrospinal fluid compartment with oxyhemoglobin being the most abundant species between day 3 and 14 after ictus. Free oxyhemoglobin in the cerebrospinal fluid compartment has been shown to induce severe macro- and microvascular constrictions in several animal studies. Previously we have found that free intravascular oxyhemoglobin substantially impedes nitric oxide-dependent vascular relaxation in isolated porcine coronary arteries and causes systemic hypertension in several in vivo models of intravascular hemolysis. Importantly, we could show that the plasma protein haptoglobin prevents oxyhemoglobin-induced nitric oxide depletion in the subendothelial space by scavenging and intraluminal compartmentalization in coronary arteries. In this study, we assess this protective mechanism as potential therapeutic approach to prevent oxyhemoglobin-induced vasoconstriction after subarachnoid hemorrhage. To do so, we have optimized an ex vivo vascular function model using isolated porcine basilary arteries. In this model, oxyhemoglobin at concentrations found in cerebrospinal fluid after aneurysmatic subarachnoid hemorrhage profoundly impairs vascular nitric oxide reactivity. However, human plasma-derived haptoglobin markedly restored nitric oxide-induced vascular relaxation. In conclusion, oxyhemoglobin scavenging through therapeutic haptoglobin administration may be a promising approach to restore physiological cerebrovascular nitric oxide reactivity and to normalize cerebral blood flow regulation after aneurysmatic subarachnoid hemorrhage.