The Impact of Collateral Therapeutics on Stroke Hemodynamics in Normotensive and Hypertensive Rats: a Step Toward Translation

Overview

Journal Front Neurol

Specialty Neurology

Date 2024 Apr 8

PMID 38585360

Authors

Marilyn J Cipolla

Ryan D Hunt

David S Liebeskind

Sarah M Tremble

Affiliations

Soon will be listed here.

Abstract

Introduction: Stroke interventions that increase collateral flow have the potential to salvage penumbral tissue and increase the number of patients eligible for reperfusion therapy. We compared the efficacy of two different collateral therapeutics during transient middle cerebral artery occlusion (tMCAO) in normotensive and hypertensive rats.

Methods: The change in collateral and core perfusion was measured using dual laser Doppler in response to either a pressor agent (phenylephrine, 10 mg/kg iv or vehicle) or a collateral vasodilator (TM5441, 5 mg/kg iv or vehicle) given 30 min into tMCAO in male Wistar and spontaneously hypertensive rats (SHRs).

Results: Pressor therapy increased collateral flow in the Wistar rats but was ineffective in the SHRs. The increase in collateral flow in the Wistar rats was associated with impaired cerebral blood flow autoregulation (CBFAR) that was intact in the SHRs. TM5441 caused a decrease in collateral perfusion in the Wistar rats and a modest increase in the SHRs. The pressor therapy reduced early infarction in both groups but increased edema in the SHRs, whereas TM5441 did not have any beneficial effects in either group.

Conclusions: Thus, the pressor therapy was superior to a collateral vasodilator in increasing collateral flow and improving outcomes in the Wistar rats, likely due to pial collaterals that were pressure passive; the lack of CBF response in the SHRs to pressor therapy was likely due to intact CBFAR that limited perfusion. While TM5441 modestly increased CBF in the SHRs but not in the Wistar rats, it did not have a beneficial effect on stroke outcomes. These results suggest that collateral therapies may need to be selected for certain comorbidities.

Citing Articles

Collateral blood vessels in stroke and ischemic disease: Formation, physiology, rarefaction, remodeling.

Faber J J Cereb Blood Flow Metab. 2025; :271678X251322378.

PMID: 40072222 PMC: 11904929. DOI: 10.1177/0271678X251322378.

Stroke in Pregnancy and Preeclampsia: Effect of Low-Dose Aspirin Treatment on Collateral Flow Velocity and Cerebral Blood Flow Autoregulation During Ischemia in Rats.

Cipolla M, Tremble S J Am Heart Assoc. 2024; 13(13):e035990.

PMID: 38934871 PMC: 11255710. DOI: 10.1161/JAHA.124.035990.

References

Castro P, Serrador J, Rocha I, Sorond F, Azevedo E . Efficacy of Cerebral Autoregulation in Early Ischemic Stroke Predicts Smaller Infarcts and Better Outcome. Front Neurol. 2017; 8:113. PMC: 5364144. DOI: 10.3389/fneur.2017.00113. View

Beard D, Li Z, Schneider A, Couch Y, Cipolla M, Buchan A . Rapamycin Induces an eNOS (Endothelial Nitric Oxide Synthase) Dependent Increase in Brain Collateral Perfusion in Wistar and Spontaneously Hypertensive Rats. Stroke. 2020; 51(9):2834-2843. PMC: 7484020. DOI: 10.1161/STROKEAHA.120.029781. View

Eames P, Blake M, Dawson S, Panerai R, Potter J . Dynamic cerebral autoregulation and beat to beat blood pressure control are impaired in acute ischaemic stroke. J Neurol Neurosurg Psychiatry. 2002; 72(4):467-72. PMC: 1737824. DOI: 10.1136/jnnp.72.4.467. View

Chan S, Bishop N, Li Z, Cipolla M . Inhibition of PAI (Plasminogen Activator Inhibitor)-1 Improves Brain Collateral Perfusion and Injury After Acute Ischemic Stroke in Aged Hypertensive Rats. Stroke. 2018; 49(8):1969-1976. PMC: 6202199. DOI: 10.1161/STROKEAHA.118.022056. View

Chan S, Sweet J, Bishop N, Cipolla M . Pial Collateral Reactivity During Hypertension and Aging: Understanding the Function of Collaterals for Stroke Therapy. Stroke. 2016; 47(6):1618-25. PMC: 4878286. DOI: 10.1161/STROKEAHA.116.013392. View

Toriumi H, Tatarishvili J, Tomita M, Tomita Y, Unekawa M, Suzuki N . Dually supplied T-junctions in arteriolo-arteriolar anastomosis in mice: key to local hemodynamic homeostasis in normal and ischemic states?. Stroke. 2009; 40(10):3378-83. DOI: 10.1161/STROKEAHA.109.558577. View

Olthuis S, Pirson F, Pinckaers F, Hinsenveld W, Nieboer D, Ceulemans A . Endovascular treatment versus no endovascular treatment after 6-24 h in patients with ischaemic stroke and collateral flow on CT angiography (MR CLEAN-LATE) in the Netherlands: a multicentre, open-label, blinded-endpoint, randomised, controlled,.... Lancet. 2023; 401(10385):1371-1380. DOI: 10.1016/S0140-6736(23)00575-5. View

Boe A, Eren M, Murphy S, Kamide C, Ichimura A, Terry D . Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence. Circulation. 2013; 128(21):2318-24. PMC: 3933362. DOI: 10.1161/CIRCULATIONAHA.113.003192. View

Petersen N, Ortega-Gutierrez S, Reccius A, Masurkar A, Huang A, Marshall R . Dynamic cerebral autoregulation is transiently impaired for one week after large-vessel acute ischemic stroke. Cerebrovasc Dis. 2015; 39(2):144-50. PMC: 4754197. DOI: 10.1159/000368595. View

10.

McCabe C, Gallagher L, Gsell W, Graham D, Dominiczak A, Macrae I . Differences in the evolution of the ischemic penumbra in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats. Stroke. 2009; 40(12):3864-8. PMC: 3145096. DOI: 10.1161/STROKEAHA.109.559021. View

11.

Hammer M, Schwamm L, Starkman S, Schellinger P, Jovin T, Nogueira R . Safety and feasibility of NeuroFlo use in eight- to 24-hour ischemic stroke patients. Int J Stroke. 2012; 7(8):655-61. PMC: 4157918. DOI: 10.1111/j.1747-4949.2011.00719.x. View

12.

Lima F, Furie K, Silva G, Lev M, Camargo E, Singhal A . The pattern of leptomeningeal collaterals on CT angiography is a strong predictor of long-term functional outcome in stroke patients with large vessel intracranial occlusion. Stroke. 2010; 41(10):2316-22. PMC: 4939434. DOI: 10.1161/STROKEAHA.110.592303. View

13.

Li Z, Tremble S, Cipolla M . Implications for understanding ischemic stroke as a sexually dimorphic disease: the role of pial collateral circulations. Am J Physiol Heart Circ Physiol. 2018; 315(6):H1703-H1712. PMC: 6336971. DOI: 10.1152/ajpheart.00402.2018. View

14.

WHEELER E, Brenner Z . Peripheral vascular anatomy, physiology, and pathophysiology. AACN Clin Issues. 1995; 6(4):505-14. DOI: 10.1097/00044067-199511000-00002. View

15.

Emery D, Schellinger P, Selchen D, Douen A, Chan R, Shuaib A . Safety and feasibility of collateral blood flow augmentation after intravenous thrombolysis. Stroke. 2011; 42(4):1135-7. DOI: 10.1161/STROKEAHA.110.607846. View

16.

Dohmen C, Bosche B, Graf R, Reithmeier T, Ernestus R, Brinker G . Identification and clinical impact of impaired cerebrovascular autoregulation in patients with malignant middle cerebral artery infarction. Stroke. 2006; 38(1):56-61. DOI: 10.1161/01.STR.0000251642.18522.b6. View

17.

Zhang H, Prabhakar P, Sealock R, Faber J . Wide genetic variation in the native pial collateral circulation is a major determinant of variation in severity of stroke. J Cereb Blood Flow Metab. 2010; 30(5):923-34. PMC: 2949178. DOI: 10.1038/jcbfm.2010.10. View

18.

Novak V, Yang A, Lepicovsky L, Goldberger A, Lipsitz L, Peng C . Multimodal pressure-flow method to assess dynamics of cerebral autoregulation in stroke and hypertension. Biomed Eng Online. 2004; 3(1):39. PMC: 529459. DOI: 10.1186/1475-925X-3-39. View

19.

Cipolla M, Chan S . Impact of Acute and Chronic Hypertension on Changes in Pial Collateral Tone In Vivo During Transient Ischemia. Hypertension. 2020; 76(3):1019-1026. PMC: 7429292. DOI: 10.1161/HYPERTENSIONAHA.120.15356. View

20.

Wilson C, Zhang X, Buckley C, Heathcote H, Lee M, McCarron J . Increased Vascular Contractility in Hypertension Results From Impaired Endothelial Calcium Signaling. Hypertension. 2019; 74(5):1200-1214. PMC: 6791503. DOI: 10.1161/HYPERTENSIONAHA.119.13791. View