Review Article

Cerebral Autoregulation in Hypertension and Ischemic Stroke: A Mini Review

Shashank Shekhar1,2, Ruen Liu3, Olivia K Travis4, Richard J Roman4 and Fan Fan4*

1Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, USA

2Institute of Clinical Medicine, University of Turku, Turku, Finland

3Department of Neurosurgery, Peking University People’s Hospital, Beijing, China

4Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA

*Corresponding author: Fan Fan, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216, USA, Tel: +1 6019842320; Fax: +1 6019841637; E-mail: ffan@umc.edu

Citation: Shekhar S, Liu R, Travis OK, Roman RJ, Fan F (2017) Cerebral Autoregulation in Hypertension and Ischemic Stroke: A Mini Review. J Pharm Sci Exp Pharmacol 2017: 21-27. doi: https://doi.org/10.29199/JAPS.101013

Received Date: 22 June, 2017; Accepted Date: 26 July, 2017; Published Date: 14 August, 2017

Abstract

Aging and chronic hypertension are associated with dysfunction in vascular smooth muscle, endothelial cells, and neurovascular coupling. These dysfunctions induce impaired myogenic response and cerebral autoregulation, which diminish the protection of large cerebral arteries and pial arterioles to the cerebral microcirculation from elevated pressure in hypertension. Chronic hypertension promotes cerebral focal ischemia in response to reductions in blood pressure that are often seen in sedentary elderly patients on antihypertensive therapy. Cerebral autoregulatory dysfunction thus evokes Blood-Brain Barrier (BBB) leakage, allowing the circulating inflammatory factors to infiltrate the brain to activate glia. The impaired cerebral autoregulation-induced inflammatory and ischemic injury could cause neuronal cell death and synaptic dysfunction which promote cognitive deficits. In this brief review, we summarize the pathogenesis and signaling mechanisms of cerebral autoregulation in hypertension and ischemic stroke-induced cognitive deficits, and discuss our new targets including 20-Hydroxyeicosatetraenoic acid (20-HETE), Gamma-Adducin (Add3) and Matrix Metalloproteinase-9 (MMP-9) that may contribute to the altered cerebral vascular function.

Keywords: Adducin; Cerebral Autoregulation; Hypertension; Matrix Metalloproteinase; Stroke; Vascular Dementia; 20-HETE

Abbreviations

BBB                    :                     Blood-Brain Barrier

20-HETE              :                    20-Hydroxyeicosatetraenoic Acid

Add3                   :                    Gamma-Adducin

MMP-9                 :                    Matrix Metalloproteinase-9

CBF                     :                    Cerebral Blood Flow

VSMCs                 :                    Vascular Smooth Muscle Cells

CPP                     :                    Cerebral Perfusion Pressure

NO                      :                    Nitric Oxide

EETs                    :                    Epoxyeicosatrienoic Acids

VGCC                   :                   Voltage-Gated Calcium Channels

TRPM4                  :                   Transient Receptor Potential Channel of Melastatin Subfamily Four

TRPC6                  :                    Transient Receptor Potential Canonical Subfamily Six

PKC                      :                   Protein Kinase C

CO                       :                   Carbon Monoxide

H+                       :                   Hydrogen Ion

K+                       :                   Potassium Ion

KATP                    :                   Adenosine Triphosphate Potassium

ATP                      :                   Adenosine Triphosphate Channel

MCAO                   :                   Middle Cerebral Artery Occlusion

NOS                     :                   Nitric Oxide Synthase

A2A                      :                   Adenosine 2A Receptor

VCI                      :                   Vascular Cognitive Impairment

VaD                     :                   Vascular Dementia

AD                       :                   Alzheimer’s Dementia

BP                       :                   Blood Pressure

AA                       :                   Arachidonic Acid

ROS                     :                   Reactive Oxygen Species

NF-kB                  :                   Nuclear Factor kappa-B

ICAM-1                :                   Intercellular Adhesion Molecule 1

VCAM-1                :                  Vascular Cell Adhesion Protein 1

SS                       :                   Salt Sensitive

CNS                     :                   Central Nervous System

SAH                     :                   Subarachnoid Hemorrhage

FHH                     :                   Faun Hooded Hypertensive

MMP                    :                   Matrix Metalloproteinase

KO                      :                   Knockout

Introduction

Approximately 795,000 strokes occur in the US each year, and there are many survivors [1]. Most of the survivors suffer from neurological damage resulting in significant limitations of daily life. The annual cost to treat stroke survivors is approximately 40 billion dollars in the US and is projected to rise [2]. Approximately 87% of strokes are ischemic [3]. Risk factors for ischemic stroke include aging, hypertension, diabetes, obesity especially with increased waist-to-hip ratio, dyslipidemia, smoking, chronic kidney disease, and other cardiovascular diseases [4]. The mechanisms that link aging, hypertension, stroke and cognitive impairments are not fully understood. There is an urgent need to understand the pathogenesis and discover novel drug targets for prevention and treatment of these devastating diseases. In this brief review, we aim to explore the cerebral autoregulatory signal mechanism and its pathogenesis in hypertension and ischemic stroke-induced cognitive deficits. We will discuss new targets including 20-Hydroxyeicosatetraenoic acid (20-HETE), Gamma-Adducin (Add3) and Matrix Metalloproteinase-9 (MMP-9) that may contribute to the cerebral vascular function.

Materials and Methods

A systemic review of the current literature was performed. We searched MEDLINE, Web of Science, and Google through June 2017 using keywords “Cerebral autoregulation, Stroke, Hypertension, Vascular Dementia, 20-HETE, adducin, Matrix Metalloproteinase”. All literature in English was reviewed excluding case-reports, and commentaries. References of included articles were further explored.

Discussion

Autoregulation of cerebral blood flow

Cerebral Autoregulation was first studied by NA Lassen in 1959 [5]. Thereafter the definition has been broadly utilized in explaining global perfusion changes or local circulatory changes [5,6]. Autoregulation of Cerebral Blood Flow (CBF) is a critical homeostatic mechanism that protects the brain from elevations in capillary hydrostatic pressure, vascular damage and cerebral edema following elevations in systemic pressure and from ischemic injury in response to embolization or hypotension [7]. It is generally accepted that autoregulation of CBF is mediated by an interplay between the myogenic response in Vascular Smooth Muscle Cells (VSMCs) acting in concert with the release of vasodilatory metabolic mediators from the surrounding hypoxic brain tissue when Cerebral Perfusion Pressure (CPP) is reduced [8,9]. In response to elevations of transmural pressure in the brain, half of the pressure drop across the cerebral circulation occurs in large arteries [7,10-12], which attenuate 75% of increases in CPP from reaching small pial arteries, and the small pial arterioles and penetrating arterioles account for the remainder of the autoregulation of CBF and capillary pressure [7,13]. On the other hand, in response to the reduction in CPP, the large cerebral arteries dilate as part of the initial cerebral autoregulation. Next, pial and penetrating arterioles, then small pial arterioles dilate following modest to severe reductions in systemic pressure [13,14], and this is mediated by the release of metabolic dilators from the surrounding hypoxic brain tissue including Nitric Oxide (NO), adenosine, prostaglandins and Epoxyeicosatrienoic acids (EETs) [15-17].

Regulating factors and signaling mechanisms of cerebral autoregulation

Myogenic response: The pressure-dependent myogenic response of cerebral vasculature is an intrinsic property of VSMCs since it can readily be demonstrated in de-endothelialized cerebral arterioles in vitro [18]. The myogenic response involves depolarization of VSMCs and calcium influx through L-type Voltage-Gated Calcium Channels (VGCC), Ca++/calmodulin-dependent phosphorylation, activation of myosin light chain kinase and actin-myosin based contraction [19,20]. There is evidence that Mechanotransduction involves an interaction of cell surface integrins with extracellular matrix proteins. Indeed, blockade of integrins inhibits calcium currents in VSMCs and myogenic tone of skeletal muscle arterioles [21,22]. Recent studies have suggested that the initiation of the myogenic response probably involves activation of nonselective stretch-activated cation channels, such as Transient Receptor Potential Channel of Melastatin Subfamily Four (TRPM4), and Transient Receptor Potential Canonical Subfamily Six (TRPC6) channels via Protein Kinase C (PKC) dependent pathway that depolarizes VSMCs past the threshold for activation of VGCCs [20,23-28]. In addition, activation of Stretch Activated Channels (SOC) and local changes in intracellular Ca++ activates the large conductance calcium-activated potassium (BK) channels [19,20], that hyperpolarize VSMCs which inactivates the L-type VGCCs and limits the myogenic response.

 

Metabolic mechanisms:Cerebral autoregulation is influenced by the release of vasodilatory mediators from the endothelium and surrounding parenchymal tissue in response to the reduction of CPP. These mediators include NO, Carbon Monoxide (CO), prostaglandins, prostacyclin, EETs, adenosine, Hydrogen ion (H+), and Potassium ion (K+) and Adenosine Triphosphate (ATP). The release of these compounds is determined by the balance between the steady state energy metabolism, dynamic fluctuations in neuronal activity, arterial PCO2 and arterial O2 content. In this regard, release of adenosine [29-31], of activation of Potassium Adenosine Triphosphate Channel (KATP) channels [32-35] and release of glutamate leading to increased production of NO have all been reported to contribute to the dilation of pial arterioles associated with hypoxia and ischemia of cerebral tissue following Middle Cerebral Artery Occlusion (MCAO) [33]. However, most of these mediators do not contribute to the metabolic component of autoregulation following CPP reduction within the autoregulatory range in which the tissue is not ischemic. Similarly, blockade of Nitric Oxide Synthase (NOS) and prostaglandins have little or no effect [36-40] on CBF following reductions in CPP in the autoregulatory range. Whereas, reductions in CPP within the autoregulatory range does increase tissue adenosine levels [41] and blockade of Adenosine Deaminase or Adenosine 2A Receptor (A2A) receptors attenuates the vasodilatory response of pial arterioles [39,42]. These results indicate that tissue hypoxia is not required for the release of adenosine. Indeed, adenosine is generated by ecto-nucleotidase enzymatic breakdown of ATP released by neurons and astrocytes [43]. Thus, perivascular generation of adenosine appears to be one of the best candidates that contribute to “metabolic” vasodilation following decreases in CPP.

Hypertension, ischemic stroke and cerebral autoregulation

Hypertension is one of the leading causes of morbidity and mortality regardless of the type of stroke [44]. Cerebral autoregulation is often impaired in hypertensive and aging individuals and contributes to the development of stroke, Vascular Cognitive Impairment (VCI) and Vascular Dementia (VaD) [45-47]. Loss of cerebral autoregulation should increase transmission of pressure to cerebral capillaries resulting in BBB leakage, cerebral edema, inflammation, and neuron degeneration that are commonly seen in patients with VCI [6,46-49]. Chronic hypertension also promotes capillary rarefaction, especially in the deep hemispheric white matter and basal ganglia [46,50]. It is associated with infiltration of perivascular macrophages, increased oxidative stress, endothelial dysfunction, and compromised functional hyperemia [48,51]. These changes promote the formation of small lacunar infarcts, white matter hyperintensities, microinfarcts, and microbleeds, all of which are correlated with a decline in cognitive function in patients with VaD and Alzheimer’s Dementia (AD) [52,53].

Trials in ischemic stroke have demonstrated that both high and lower systolic blood pressure is associated with poor outcomes [54]. The blood pressure plot vs outcomes of ischemic stroke in two different studies demonstrated a ‘U shape’ curve, and a better outcome only exhibited within a very narrow range of Blood Pressure (BP) between 150 mm Hg [54] and 180 mm Hg recorded at the time of the first encounter in emergency [55]. These results along with other studies suggest that increased sympathetic drive is necessary during and immediately after acute stroke attack to maintain a normal cerebral autoregulation for the maintenance of adequate tissue perfusion and expect a better outcome of stroke [54,56,57]. This hypothesis has been confirmed in many experiments that rapid drop in BP may result in extended infarction due to perilesional ischemia [55,58,59] and increased risk of hemorrhagic transformation [60] in stroke patients with preexhibited cerebral autoregulatory dysfunction, which later results in the pathogenesis of cognitive deficits including vascular dementia [61].

Genes contributing to cerebral autoregulation

Many factors including the role of endothelial dysfunction and hyperemia have been implicated in the regulation of cerebral autoregulation [18,19]. Recent studies have also revealed that several genes may be involved in the myogenic response of cerebral arteries and autoregulation of CBF that may contribute to the pathogenesis of ischemic stroke and cognitive impairment in hypertension and aging. In this review, we focus on the role of 20-HETE, adducin and MMP.

Cytochrome P450 (CYP) 4A and 4F: Enzymes of CYP4A and CYP4F catalyze Arachidonic Acid (AA) to produce 20-HETE. In the Central Nervous System (CNS), 20-HETE is produced primarily in the VSMCs, neurons, and astrocytes [62-64]. It is a potent vasoconstrictor that potentiates the response to angiotensin II and endothelin and ATP, as well as vascular hypertrophy, endothelial dysfunction, angiogenesis, inflammation, apoptosis and platelet aggregation [18-20]. Plasma level of 20-HETE level in plasma increases after acute ischemic stroke [65]. A higher level of 20-HETE promotes inflammation by the production of Reactive Oxygen Species (ROS) and Nuclear Factor kappa-B (NF-kB) in the cerebral vasculature [66]. It also increases cytokines production and expression of Intercellular Adhesion Molecule 1 (ICAM-1) and Vascular Cell Adhesion Protein 1 (VCAM-1) on B-lymphocytes [67,68] and adhesion molecules in endothelial cells [69,70] which further promotes margination of macrophages and enhancing inflammatory cascade. Functional genetic variants in CYP4F2 and CYP4A11 that decreases the formation of 20-HETE are linked to hypertension [71,72] and stroke [19,20,73]. Results from animal studies are consistent with these findings in patients. The formation of 20-HETE is reduced in the cerebral vasculature of Dahl Salt Sensitive (SS) rats, and these rats exhibit impaired myogenic response of cerebral arteries and autoregulation of CBF, as well as an increase of BBB leakage in response to elevations in cerebral perfusion pressure [74]. Transfer of wild type CYP4A genes in a chromosome 5 consomic strain or introduction of a wild type of CYP4A1 gene in a transgenic SS strain, restores the production of 20-HETE, autoregulation of CBF and rescues BBB leakage [74]. Recent epidemiological studies have shown associations between genetic variants in the genes that produce 20 HETE with stroke [73], and associated cognitive impairment [75]. Furthermore, 20-HETE is associated with unfavorable outcome in subarachnoid hemorrhage patient, likely from acute and delayed cerebral vasospasm after Subarachnoid Hemorrhage (SAH) [76].

Adducin: Adducin is a cytoskeletal protein that comprises of heterodimers of Alpha-adducin (Add1) with either Beta-adducin (Add2) or Gamma-adducin (Add3). It plays roles in the organization of cytoskeletal structure, the formation of the cell to cell contact and cell migration and signal transduction [77]. The heterodimers of Add1 and Add3 promotes actin-spectrin interactions and regulates actin polymerization [77,78]. Functional variants of Add1 have been linked to the development of hypertension in Milan hypertensive rats and humans [79] by altering the localization of plasma membrane and activity of Na+/K+-ATPase [80]. More recently, our lab has identified a genetic variant of Add3 in Fawn Hooded Hypertensive (FHH) rats that are associated with impaired myogenic response and autoregulation of renal and cerebral blood flow [81-83]. In addition, knockdown of Add3 expression in both renal and cerebral arteries in normal rats diminishes their myogenic responses ex vivo and enhances BK channels activity [78]. Moreover, our recent preliminary work indicated that downregulation of Add3 in FHH rats is associated with an elevation in transmission pressure in the terminal of arteries and the development of cognitive impairments following the development of hypertension with age [84].

Matrix metalloproteinases: The Matrix Metalloproteinase (MMP) family of zinc-binding proteolytic enzymes degrade collagen and fibronectin [85]. They regulate neutrophil migration across the basement membrane and play an important role in angiogenesis and extracellular matrix remodeling associated with various physiological or pathological processes [86,87]. MMPs are known to play a role in the pathogenesis of atherosclerosis, coronary artery disease and cerebral vascular injury [88,89]. The expression of MMP-2 and MMP-9 are increased in neurons, astrocytes, and microglia [90] following ischemic stroke and intracerebral hemorrhage. Inhibition of MMP-9 reduces infarct size in ischemic stroke rat models [91,92]. MMP9 polymorphism has been reported to significantly increase the risk of ischemic stroke in Type 2 diabetes [93], and is associated with detrimental functional outcomes in altering the severity of infarct size after the onset of ischemic stroke [89,94]. Moreover, thrombolysis (t-PA) has been reported to enhance MMP-9 release which further enhances neuronal damage resulting in edema and hemorrhagic transformation [95]. MMP9 is associated with mild cognitive impairment and VCI [96-98]. Whereas, treatment with human cord plasma containing MMP-2 inhibitor restores the hippocampal function and improves cognition in aged mice [99].

The role of MMPs in hypertension and ischemic stroke-induced cognitive deficits is multifactorial. Mechanistically, MMPs activate migration and proliferation of VSMCs [85,89], and facilitate inflammation and perivascular fibrosis [100]. Whether they regulate cerebral autoregulation has not been elucidated. Elevated levels of MMP-9 have been found in SS rats, inhibition of MMP-9 reduces oxidative stress and endothelial dysfunction and attenuates cerebrovascular dysfunction in this strain after the development of hypertension [101]. Knockout (KO) of MMP-9 protects against ischemic and traumatic brain injury in mice and is mediated by reduced BBB leakage and white matter damage [85]. Results from our recent studies in MMP-9 KO SS rats are consistent with these findings. Furthermore, we found that the impaired myogenic response and autoregulation of CBF in hypertensive SS rats are restored in the MMP-9 KO strain [102]. Inhibition of MMP-9 now is examined as a therapeutic strategy in ischemic stroke [103].

Conclusion

Cerebral vascular dysfunction is a rising concern that contributes to cognitive impairments, including Alzheimer’s disease and vascular dementia. Hypertension and ischemic stroke-induced cognitive deficits are often associated with impaired myogenic response and autoregulation of CBF. Genetic variants in genes involved in regulation of cerebrovascular function are linked to hypertension, stroke, and dementia. Understanding the vascular pathogenesis may help to explore novel drug targets to delay the onset and prevent the progression and severity of these currently incurable diseases.

Acknowledgments

This study was supported by grants AG050049 (Fan), P20GM104357 (Fan and Roman), HL36279 (Roman) and DK104184 (Roman) from the National Institutes of Health and 16GRNT31200036 (Fan) from the American Heart Association.

 

References

  1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, et al. (2017) Heart Disease and Stroke Statistics-2017 Update: A Report from the American Heart Association. Circulation 135: 146-603.
  2. Skolarus LE, Freedman VA, Feng C, Wing JJ, Burke JF (2016) Care Received by Elderly US Stroke Survivors May Be Underestimated. Stroke 47: 2090-2095.
  3. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, et al. (2015) Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Circulation 131: 29-322.
  4. Feigin VL, Lawes CM, Bennett DA, Anderson CS (2003) Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2: 43-53.
  5. Lassen NA (1959) Cerebral blood flow and oxygen consumption in man. Physiol Rev 39: 183-238.
  6. Shekhar S, Wang S, Mims PN, Gonzalez-Fernandez E, Zhang C, et al. (2017) Impaired Cerebral Autoregulation-A Common Neurovascular Pathway in Diabetes may Play a Critical Role in Diabetes-Related Alzheimer’s Disease. Curre Res Diabetes & Obes J 2: 555587.
  7. Faraci FM, Mayhan WG, Heistad DD (1987) Segmental vascular responses to acute hypertension in cerebrum and brain stem. Am J Physiol 252: 738-742.
  8. Dacey RG Jr, Duling BR (1982) A study of rat intracerebral arterioles: methods, morphology, and reactivity. Am J Physiol 243: 598-606.
  9. Thorin-Trescases N, Bartolotta T, Hyman N, Penar PL, Walters CL, et al. (1997) Diameter dependence of myogenic tone of human pial arteries. Possible relation to distensibility. Stroke 28: 2486-2492.
  10. Harper SL, Bohlen HG, Rubin MJ (1984) Arterial and microvascular contributions to cerebral cortical autoregulation in rats. Am J Physiol 246: 17-24.
  11. Hurn PD, Traystman RJ, Shoukas AA, Jones MD (1993) Pial microvascular hemodynamicsin anemia. Am J Physiol 264: 2131-2135.
  12. Shapiro HM, Stromberg DD, Lee DR, Wiederhielm CA (1971) Dynamic pressures in the pial arterial microcirculation. Am J Physiol 221: 279-283.
  13. Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, et al. (1978) Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol 234: 371-383.
  14. Baumbach GL, Heistad DD (1985) Regional, segmental, and temporal heterogeneity of cerebral vascular autoregulation. Ann Biomed Eng 13: 303-310.
  15. McPherson RW, Koehler RC, Traystman RJ (1988) Effect of jugular venous pressure on cerebral autoregulation in dogs. Am J Physiol 255: 1516-1524.
  16. Wagner EM, Traystman RJ (1986) Hydrostatic determinants of cerebral perfusion. Crit Care Med 14: 484-490.
  17. Wei EP, Kontos HA (1982) Responses of cerebral arterioles to increased venous pressure. Am J Physiol 243: 442-447.
  18. Roman RJ (2002) P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 82: 131-185.
  19. Fan F, Ge Y, Lv W, Elliott MR, Muroya Y, et al. (2016) Molecular mechanisms and cell signaling of 20-hydroxyeicosatetraenoic acid in vascular pathophysiology. Front in Biosci 21: 1427-1463.
  20. Fan F, Muroya Y, Roman RJ (2015) Cytochrome P450 eicosanoids in hypertension and renal disease. Curr Opin Nephrol Hypertens 24: 37-46.
  21. Mogford JE, Davis GE, Platts SH, Meininger GA (1996) Vascular smooth muscle alpha v beta 3 integrin mediates arteriolar vasodilation in response to RGD peptides. Circ Res 79: 821-826.
  22. Davis MJ, Hill MA (1999) Signaling mechanisms underlying the vascular myogenic response. Physiol Rev 79: 387-423.
  23. Brayden JE, Earley S, Nelson MT, Reading S (2008) Transient Receptor Potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow. Clin Exp Pharmacol Physiol 35: 1116-1120.
  24. Earley S, Straub SV, Brayden JE (2007) Protein kinase C regulates vascular myogenic tone through activation of TRPM4. Am J Physiol Heart Circ Physiol 292: 2613-2622.
  25. Earley S, Waldron BJ, Brayden JE (2004) Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ Res 95: 922-929.
  26. Murphy TV, Spurrell BE, Hill MA (2002) Cellular signalling in arteriolar myogenic constriction: involvement of tyrosine phosphorylation pathways. Clin Exp Pharmacol Physiol 29: 612-619.
  27. Hill MA, Davis MJ, Meininger GA, Potocnik SJ, Murphy TV (2006) Arteriolar myogenic signalling mechanisms: Implications for local vascular function. Clin Hemorheol Microcirc 34: 67-79.
  28. Fan F, Roman RJ (2017) GPR75 Identified as the First 20-HETE Receptor: A Chemokine Receptor Adopted by a New Family. Circ Res 120: 1696-1698.
  29. Hoffman WE, Albrecht RF, Miletich DJ (1984) The role of adenosine in CBF increases during hypoxia in young vs aged rats. Stroke 15: 124-129.
  30. Phillis JW, DeLong RE, Towner JK (1985) Adenosine deaminase inhibitors enhance cerebral anoxic hyperemia in the rat. J Cereb Blood Flow Metab 5: 295-299.
  31. Winn HR, Rubio R, Berne RM (1981) Brain adenosine concentration during hypoxia in rats. Am J Physiol 241: 235-242.
  32. Shankar V, Armstead WM (1995) Opioids contribute to hypoxia-induced pial artery dilation through activation of ATP-sensitive K+ channels. Am J Physiol 269: 997-1002.
  33. Armstead WM (1997) Role of nitric oxide, cyclic nucleotides, and the activation of ATP-sensitive K+ channels in the contribution of adenosine to hypoxia-induced pial artery dilation. J Cereb Blood Flow Metab 17: 100-108.
  34. Taguchi H, Heistad DD, Kitazono T, Faraci FM (1994) ATP-sensitive K+ channels mediate dilatation of cerebral arterioles during hypoxia. Circ Res 74: 1005-1008.
  35. Tomiyama Y, Brian JE Jr, Todd MM (1999) Cerebral blood flow during hemodilution and hypoxia in rats: role of ATP-sensitive potassium channels. Stroke 30: 1942-1947; discussion 1947-1948.
  36. Jones SC, Easley KA, Radinsky CR, Chyatte D, Furlan AJ, et al. (2003) Nitric oxide synthase inhibition depresses the height of the cerebral blood flow-pressure autoregulation curve during moderate hypotension. J Cereb Blood Flow Metab 23: 1085-1095.
  37. Jones SC, Radinsky CR, Furlan AJ, Chyatte D, Perez-Trepichio AD (1999) Cortical NOS inhibition raises the lower limit of cerebral blood flow-arterial pressure autoregulation. Am J Physiol 276: 1253-1262.
  38. Saito S, Wilson DA, Hanley DF, Traystman RJ (1994) Nitric oxide synthase does not contribute to cerebral autoregulatory phenomenon in anesthetized dogs. J Auton Nerv Syst 49: 73-76.
  39. Shin HK, Shin YW, Hong KW (2000) Role of adenosine A(2B) receptors in vasodilation of rat pial artery and cerebral blood flow autoregulation. Am J Physiol Heart Circ Physiol 278: 339-344.
  40. Wang Q, Paulson OB, Lassen NA (1992) Is autoregulation of cerebral blood flow in rats influenced by nitro-L-arginine, a blocker of the synthesis of nitric oxide? Acta Physiol Scand 145: 297-298.
  41. Winn HR, Welsh JE, Rubio R, Berne RM (1980) Brain adenosine production in rat during sustained alteration in systemic blood pressure. Am J Physiol 239: 636-641.
  42. Kontos HA, Wei EP (1985) Oxygen-dependent mechanisms in cerebral autoregulation. Ann Biomed Eng 13: 329-334.
  43. Xu HL, Pelligrino DA (2007) ATP release and hydrolysis contribute to rat pial arteriolar dilatation elicited by neuronal activation. Exp Physiol 92: 647-651.
  44. Mullen MT, McKinney JS, Kasner SE (2009) Blood pressure management in acute stroke. J Hum Hypertens 23: 559-569.
  45. Strandgaard S, Olesen J, Skinhoj E, Lassen NA (1973) Autoregulation of brain circulation in severe arterial hypertension. Br Med J 1: 507-510.
  46. Faraco G, Iadecola C (2013) Hypertension: a harbinger of stroke and dementia. Hypertension 62: 810-817.
  47. Lammie GA (2002) Hypertensive cerebral small vessel disease and stroke. Brain Pathol 12: 358-370.
  48. Iadecola C (2014) Hypertension and dementia. Hypertension 64: 03-05.
  49. Paulson OB, Strandgaard S, Edvinsson L (1990) Cerebral autoregulation. Cerebrovasc Brain Metab Rev 2: 161-192.
  50. Federico A, Di Donato I, Bianchi S, Di Palma C, Taglia I, et al. (2012) Hereditary cerebral small vessel diseases: a review. J Neurol Sci 322: 25-30.
  51. Pires PW, Dams Ramos CM, Matin N, Dorrance AM (2013) The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol 304: 1598-1614.
  52. Hainsworth AH, Markus HS (2008) Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review. J Cereb Blood Flow Metab 28: 1877-1891.
  53. Strandgaard S (1991) Cerebral blood flow in the elderly: Impact of hypertension and antihypertensive treatment. Cardiovasc Drugs Ther 4: 1217-1221.
  54. Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock PA, IST Collaborative Group (2002) Blood pressure and clinical outcomes in the International Stroke Trial. Stroke 33: 1315-1320.
  55. Castillo J, Leira R, Garcia MM, Serena J, Blanco M, et al. (2004) Blood pressure decrease during the acute phase of ischemic stroke is associated with brain injury and poor stroke outcome. Stroke 35: 520-526.
  56. Qureshi AI, Ezzeddine MA, Nasar A, Suri MF, Kirmani JF, et al. (2007) Prevalence of elevated blood pressure in 563,704 adult patients with stroke presenting to the ED in the United States. Am J Emerg Med 25: 32-38.
  57. Dawson SL, Panerai RB, Potter JF (2003) Serial changes in static and dynamic cerebral autoregulation after acute ischaemic stroke. Cerebrovasc Dis 16: 69-75.
  58. Owens WB (2011) Blood pressure control in acute cerebrovascular disease. J Clin Hypertens 13: 205-211.
  59. Oliveira-Filho J, Silva SC, Trabuco CC, Pedreira BB, Sousa EU, et al. (2003) Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset. Neurology 61: 1047-1051.
  60. Willmot M, Leonardi-Bee J, Bath PM (2004) High blood pressure in acute stroke and subsequent outcome: a systematic review. Hypertension 43: 18-24.
  61. Moretti R, Torre P, Antonello RM, Manganaro D, Vilotti C, et al. (2008) Risk factors for vascular dementia: hypotension as a key point. Vasc Health Risk Manag 4: 395-402.
  62. Renic M, Kumar SN, Gebremedhin D, Florence MA, Gerges NZ, et al. (2012) Protective effect of 20-HETE inhibition in a model of oxygen-glucose deprivation in hippocampal slice cultures. Am J Physiol Heart Circ Physiol 302: 1285-1293.
  63. Zhang H, Falck JR, Roman RJ, Harder DR, Koehler RC, et al. (2017) Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen-Glucose Deprivation in Cortical Neurons. Cell Mol Neurobiol doi: 10.1007/s10571-017-0462-8.
  64. Gebremedhin D, Zhang DX, Carver KA, Rau N, Rarick KR, et al. (2016) Expression of CYP 4A omega-hydroxylase and formation of 20-hydroxyeicosatetreanoic acid (20-HETE) in cultured rat brain astrocytes. Prostaglandins Other Lipid Mediat 124: 16-26.
  65. Yi X, Han Z, Zhou Q, Lin J, Liu P (2016) 20-Hydroxyeicosatetraenoic Acid as a Predictor of Neurological Deterioration in Acute Minor Ischemic Stroke. Stroke 47: 3045-3047.
  66. Toth P, Csiszar A, Sosnowska D, Tucsek Z, Cseplo P, et al. (2013) Treatment with the cytochrome P450 omega-hydroxylase inhibitor HET0016 attenuates cerebrovascular inflammation, oxidative stress and improves vasomotor function in spontaneously hypertensive rats. Br J Pharmacol 168: 1878-1888.
  67. Zhu P, Liu X, Labelle EF, Freedman BD (2005) Mechanisms of hypotonicity-induced calcium signaling and integrin activation by arachidonic acid-derived inflammatory mediators in B cells. J Immunol 175: 4981-4989.
  68. Liu X, Zhu P, Freedman BD (2006) Multiple eicosanoid-activated nonselective cation channels regulate B-lymphocyte adhesion to integrin ligands. Am J Physiol Cell Physiol 290: 873-882.
  69. Ishizuka T, Cheng J, Singh H, Vitto MD, Manthati VL, et al. (2008) 20-Hydroxyeicosatetraenoic acid stimulates nuclear factor-kappaB activation and the production of inflammatory cytokines in human endothelial cells. J Pharmacol Exp Ther 324: 103-110.
  70. Wang J, Li H, He J, Li B, Bao Q, et al. (2015) 20-Hydroxyeicosatetraenoic acid involved in endothelial activation and thrombosis. Am J Physiol Heart Circ Physiol 308: 1359-1367.
  71. Gainer JV, Bellamine A, Dawson EP, Womble KE, Grant SW, et al. (2005) Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension. Circulation 111: 63-69.
  72. Ward NC, Tsai IJ, Barden A, van Bockxmeer FM, Puddey IB, et al. (2008) A single nucleotide polymorphism in the CYP4F2 but not CYP4A11 gene is associated with increased 20-HETE excretion and blood pressure. Hypertension 51: 1393-1398.
  73. Ding H, Cui G, Zhang L, Xu Y, Bao X, et al. (2010) Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population. Pharmacogenet Genomics 20: 187-194.
  74. Fan F, Geurts AM, Murphy SR, Pabbidi MR, Jacob HJ, et al. (2015) Impaired myogenic response and autoregulation of cerebral blood flow is rescued in CYP4A1 transgenic Dahl salt-sensitive rat. Am J Physiol Regul Integr Comp Physiol 308: 379-390.
  75. Fan F, Simino J, Auchus A, Knopman D, Boerwinkle E, et al. (2016) Functional variants in CYP4A11 and CYP4F2 are associated with cognitive impairment and related dementia endophenotypes in the elderly. The 16th International Winter Eicosanoid Conference, Baltimore, USA.
  76. Roman RJ, Renic M, Dunn KM, Takeuchi K, Hacein-Bey L (2006) Evidence that 20HETE contributes to the development of acute and delayed cerebral vasospasm. Neurol Res 28: 738-749.
  77. Matsuoka Y, Li X, Bennett V (2000) Adducin: structure, function and regulation. Cell Mol Life Sci 57: 884-895.
  78. Fan F, Pabbidi MR, Ge Y, Li L, Wang S, et al. (2017) Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries. Am J Physiol Renal Physiol 312: 971-981.
  79. Bianchi G, Tripodi G (2003) Genetics of hypertension: the adducin paradigm. Ann NY Acad Sci 986: 660-668.
  80. Ferrandi M, Salardi S, Tripodi G, Barassi P, Rivera R, et al. (1999) Evidence for an interaction between adducin and Na(+)-K (+)-ATPase: relation to genetic hypertension. Am J Physiol 277: 1338-1349.
  81. Burke M, Pabbidi M, Fan F, Ge Y, Liu R, et al. (2013) Genetic basis of the impaired renal myogenic response in FHH rats. Am J Physiol Renal Physiol 304: 565-577.
  82. Fan F, Geurts A, Pabbidi M, Ge Y, Harder D, et al. (2015) Abstract MP14: A K572Q Mutation in Gamma-adducin Is Responsible for the Impaired Myogenic Response and Autoregulation of Renal and Cerebral Blood Flow in FHH Rats. Hypertension 66: AMP14.
  83. Pabbidi MR, Juncos J, Juncos L, Renic M, Tullos HJ, et al. (2013) Identification of a region of rat chromosome 1 that impairs the myogenic response and autoregulation of cerebral blood flow in fawn-hooded hypertensive rats. Am J Physiol Heart Circ Physiol 304: 311-317.
  84. Fan F, Pabbidi M, Lin RCS, Ge Y, Gomez-Sanchez EP, et al. (2016) Impaired myogenic response of MCA elevates transmission of pressure to penetrating arterioles and contributes to cerebral vascular disease in aging hypertensive FHH rats. The FASEB Journal 30: 953-957.
  85. Galis ZS, Khatri JJ (2002) Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 90: 251-262.
  86. Raffetto JD, Khalil RA (2008) Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 75: 346-359.
  87. Sang QX (1998) Complex role of matrix metalloproteinases in angiogenesis. Cell research 8: 171-177.
  88. Blankenberg S, Rupprecht HJ, Poirier O, Bickel C, Smieja M, et al. (2003) Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 107: 1579-1585.
  89. Katakami N, Takahara M, Kaneto H, Shimizu I, Ohno K, et al. (2010) Accumulation of gene polymorphisms related to plaque disruption and thrombosis is associated with cerebral infarction in subjects with type 2 diabetes. Diabetes Care 33: 390-395.
  90. Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7: 97.
  91. Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 29: 1020-1030.
  92. Fatar M, Stroick M, Griebe M, Hennerici M (2005) Matrix metalloproteinases in cerebrovascular diseases. Cerebrovasc Dis 20: 141-151.
  93. Buraczynska K, Kurzepa J, Ksiazek A, Buraczynska M, Rejdak K (2015) Matrix Metalloproteinase-9 (MMP-9) Gene Polymorphism in Stroke Patients. Neuromolecular Med 17: 385-390.
  94. Kaplan RC, Smith NL, Zucker S, Heckbert SR, Rice K, et al. (2008) Matrix Metalloproteinase-3 (MMP3) and MMP9 genes and risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke. Atherosclerosis 201: 130-137.
  95. Lee SR, Tsuji K, Lee SR, Lo EH (2004) Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J Neurosci 24: 671-678.
  96. Bruno MA, Mufson EJ, Wuu J, Cuello AC (2009) Increased matrix metalloproteinase 9 activity in mild cognitive impairment. J Neuropathol Exp Neurol 68: 1309-1318.
  97. Rosenberg GA (2016) Matrix Metalloproteinase-Mediated Neuroinflammation in Vascular Cognitive Impairment of the Binswanger Type. Cell Mol Neurobiol 36: 195-202.
  98. Adair JC, Charlie J, Dencoff JE, Kaye JA, Quinn JF, et al. (2004) Measurement of gelatinase B (MMP-9) in the cerebrospinal fluid of patients with vascular dementia and Alzheimer disease. Stroke 35: 159-162.
  99. Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, et al. (2017) Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544: 488-492.
  100. Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML (2013) Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiology 28: 391-403.
  101. Kalani A, Pushpakumar SB, Vacek JC, Tyagi SC, Tyagi N (2016) Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats. Mol Cell Biochem 413: 25-35.
  102. Joo IL, Lai AY, Bazzigaluppi P, Koletar MM, Dorr A, et al. (2017) Early neurovascular dysfunction in a transgenic rat model of Alzheimer’s disease. Sci Rep 7: 46427.
  103. Chaturvedi M, Kaczmarek L (2014) Mmp-9 inhibition: a therapeutic strategy in ischemic stroke. Mol Neurobiol 49: 563-573.