Pial Collateral Reactivity During Hypertension and Aging Understanding the Function of Collaterals for Stroke Therapy

Collateral perfusion is emerging as a key variable in outcome from acute ischemic stroke. Collateral status at the time of occlusion has been shown to be the strongest predictor for therapeutic recanalization and is being considered for use in clinical decision making in stroke treatment. Importantly, patients with good collateral flow or a favorable pattern of leptomeningeal collateral vessels on computed tomographic angiography have better reperfusion, smaller infarcts, and less hemorrhagic transformation, whereas patients with poor collateral status do poorly even if recanalization is achieved. Although several collateral systems exist within the brain vasculature, it is generally recognized that the leptomeningeal arterioles (LMAs) are particularly important for stroke outcome. LMAs are secondary collaterals that connect distal branches of major cerebral artery territories. During middle cerebral artery occlusion (MCAO), LMA anastomoses promote flow from the anterior cerebral artery (ACA) territory to sustain flow to the penumbra, a region of constrained blood supply that is potentially salvageable if reperfusion occurs rapidly or neuroprotective agents are present to arrest cell death. In fact, the primary goal of neuroprotection for acute stroke is to salvage penumbral tissue at risk of infarction, further highlighting a critical role of LMAs in acute stroke therapy. The ability to sustain or promote penumbral flow has been attributed to passive increases in bidirectional flow during an occlusion (eg, from ACA to MCA territories) that varies depending on the size and number of LMAs. In addition, expansion of infarct to incorporate the penumbra has been attributed to collateral failure, but factors that contribute to this process are largely unknown because of our limited understanding of the vascular biology of LMAs. In contrast to nonanastomotic pial arterioles that have been more extensively studied, LMAs experience unique hemodynamic forces, including low shear stress and bidirectional flow. The influence of this unique environment may be associated with distinct functional properties of LMAs that could significantly influence collateral perfusion, penumbral flow, and Background and Purpose—We investigated vasoactive properties of leptomeningeal arterioles (LMAs) under normotensive conditions and during hypertension and aging that are known to have poor collateral flow and little salvageable tissue. Methods—LMAs, identified as distal anastomotic arterioles connecting middle and anterior cerebral arteries, were studied isolated and pressurized from young (18 weeks) or aged (48 weeks) normotensive Wistar Kyoto (WKY18, n=14; WKY48, n=6) rats and spontaneously hypertensive rats (SHR18, n=16; SHR48, n=6). Myogenic tone and vasoactive responses to pressure as well as endothelial function and ion channel activity were measured. Results—LMAs from WKY18 had little myogenic tone at 40 mm Hg (8±3%) that increased in aged WKY48 (30±6%). However, LMAs from both WKY groups dilated to increased pressure and demonstrated little myogenic reactivity, a response that would be conducive to collateral flow. In contrast, LMAs from both SHR18 and SHR48 displayed considerable myogenic tone (56±8% and 43±7%; P<0.01 versus WKY) and constricted to increased pressure. LMAs from both WKY and SHR groups had similar basal endothelial nitric oxide and IK channel activity that opposed tone. However, dilation to sodium nitroprusside, diltiazem and 15 mmol/L KCl was impaired in LMAs from SHR18. Conclusions—This study shows for the first time that LMAs from young and aged SHR are vasoconstricted and have impaired vasodilatory responses that may contribute to greater perfusion deficit and little penumbral tissue. These results also suggest that therapeutic opening of pial collaterals is possible during middle cerebral artery occlusion to create penumbral tissue and prevent infarct expansion. (Stroke. 2016;47:1618-1625. DOI: 10.1161/STROKEAHA.116.013392.)