VAP‐1 Blockade Prevents Subarachnoid Hemorrhage‐associated Cerebrovascular Dilating Dysfunction via Repression of a Neutrophil Recruitment–Related Mechanism

Abstract

Our previous findings indicated that in rats subjected to subarachnoid hemorrhage (SAH), suppression of post-SAH neuroinflammation via vascular adhesion protein-1 (VAP-1) blockade provides significant neuroprotection. In the present study, we tested the hypotheses that: (1) treatment with LJP-1586, a selective VAP-1 blocker, prevents SAH-associated pial arteriolar dilating dysfunction; and (2) the vasculoprotective effect of LJP-1586 arises from inhibiting SAH-elicited neutrophil recruitment. Rats subjected to SAH were treated with either LJP-1586 or rendered neutropenic via anti-neutrophil-antibody. At 48h post-SAH, rats were evaluated for pial venular leukocyte trafficking, pial arteriolar reactivity to the topically-applied vasodilators, and neurologic function. Pial arteriolar responses decreased at 48h post-SAH. However, those responses were significantly preserved with LJP-1586. Neutrophil-depletion yielded a substantial suppression of SAH-associated leukocyte adhesion. This was accompanied by a significant preservation of pial arteriolar dilating function, suggesting a direct link between neutrophil recruitment and the loss of cerebral microvascular reactivity. Moreover, neutrophil depletion also was associated with significant protection of neurobehavioral function. In summary, present findings suggest that attenuating SAH-linked elevation in neutrophil trafficking will protect against the development of microvascular dysfunction and subsequent exacerbation of neurological dysfunction.