Abstract TP111: Haptoglobin Improves Intracerebral Hemorrhage Outcomes by Modulating Angiogenic Responses

Abstract

Intracerebral hemorrhage (ICH) most often occurs spontaneously and is one of the most devastating stroke subtypes. Following ICH, toxic blood components must be cleared from the brain as part of the tissue repair/scar formation healing process. Angiogenesis is a key physiologic mechanism that facilitates tissue repair following acute injury, but must be tightly regulated to prevent excessive activity and deleterious consequences. After ICH, regulation of angiogenesis within the appropriate range in injured brain regions would allow for delivery of glucose and oxygen to support the energy-requiring reparative processes and facilitate the necessary entry of peripheral cells involved. Haptoglobin (Hp) is an acute phase protein that binds extracorpuscular hemoglobin, thereby directly reducing its oxidative potential, and Hp has also been shown to have potent angiogenic, vasculogenic, and wound healing properties. Using the autologous blood model of ICH, we have shown that Hp overexpression significantly improves ICH outcomes and reduces oxidative processes. Here, we aimed to confirm our previous results and further characterize the mechanisms by which Hp exerts these neuroprotective effects. Hp was overexpressed in the brain using adeno-associated viral vectors and ICH was induced using the collagenase-induced spontaneous bleeding model, which is accompanied by clinically relevant intraventricular hemorrhage. In line with our previous study, Hp-overexpressing mice demonstrate significantly smaller lesion volumes (p<0.01) and less residual blood (p<0.05). This reduced ICH-induced brain injury is accompanied by trends towards improved ambulatory ability and less focal neurological deficits at 72h post-ICH (p<0.07). Hp-overexpressing mice have significantly reduced PECAM-1 expression and tend to have less VEGF immunoreactivity. After correcting for lesion volume, Hp-overexpressing mice retain the decreased PECAM-1 expression, but VEGF expression is increased, collectively suggesting a direct role of Hp in positively modulating angiogenesis after ICH. Hp therapy could represent a new treatment strategy for ICH through a multifactorial mechanism that includes the modulation of important angiogenic processes.