The Unexpected Role of the Endothelial Nitric Oxide Synthase at the Neurovascular Unit: Beyond the Regulation of Cerebral Blood Flow
Abstract
:1. Introduction
2. Cerebral Circulation and the NVU
3. NOS Isoforms and NO Signaling at the NVU
3.1. nNOS and eNOS: Cellular Localization within the NVU and Mechanisms of Synaptic Activation
3.2. eNOS Signaling within the NVU
3.3. The Regulation of CBF by eNOS
3.4. The Regulation of Synaptic Plasticity by eNOS
3.5. The Role of eNOS in Vascular-to-Neuronal Communication
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Furchgott, R.F.; Zawadzki, J.V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980, 288, 373–376. [Google Scholar] [CrossRef] [PubMed]
- Ignarro, L.J.; Buga, G.M.; Wood, K.S.; Byrns, R.E.; Chaudhuri, G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc. Natl. Acad. Sci. USA 1987, 84, 9265–9269. [Google Scholar] [CrossRef] [PubMed]
- Katsuki, S.; Arnold, W.; Mittal, C.; Murad, F. Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J. Cycl. Nucleotide Res. 1977, 3, 23–35. [Google Scholar]
- Ignarro, L.J. Nitric oxide is not just blowing in the wind. Br. J. Pharmacol. 2019, 176, 131–134. [Google Scholar] [CrossRef] [PubMed]
- Kisler, K.; Nelson, A.R.; Montagne, A.; Zlokovic, B.V. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 2017, 18, 419–434. [Google Scholar] [CrossRef] [PubMed]
- Kourosh-Arami, M.; Hosseini, N.; Mohsenzadegan, M.; Komaki, A.; Joghataei, M.T. Neurophysiologic implications of neuronal nitric oxide synthase. Rev. Neurosci. 2020, 31, 617–636. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Chen, Z.; Xiong, Y.; Zhou, Q.; Zhu, L.Q.; Liu, D. The emerging role of nitric oxide in the synaptic dysfunction of vascular dementia. Neural Regen. Res. 2025, 20, 402–415. [Google Scholar] [CrossRef] [PubMed]
- Iova, O.M.; Marin, G.E.; Lazar, I.; Stanescu, I.; Dogaru, G.; Nicula, C.A.; Bulboaca, A.E. Nitric Oxide/Nitric Oxide Synthase System in the Pathogenesis of Neurodegenerative Disorders-An Overview. Antioxidants 2023, 12, 753. [Google Scholar] [CrossRef] [PubMed]
- Mancardi, D.; Pla, A.F.; Moccia, F.; Tanzi, F.; Munaron, L. Old and new gasotransmitters in the cardiovascular system: Focus on the role of nitric oxide and hydrogen sulfide in endothelial cells and cardiomyocytes. Curr. Pharm. Biotechnol. 2011, 12, 1406–1415. [Google Scholar] [CrossRef] [PubMed]
- Iadecola, C. The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron 2017, 96, 17–42. [Google Scholar] [CrossRef] [PubMed]
- Soda, T.; Brunetti, V.; Berra-Romani, R.; Moccia, F. The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives. Int. J. Mol. Sci. 2023, 24, 3914. [Google Scholar] [CrossRef]
- Chow, B.W.; Nunez, V.; Kaplan, L.; Granger, A.J.; Bistrong, K.; Zucker, H.L.; Kumar, P.; Sabatini, B.L.; Gu, C. Caveolae in CNS arterioles mediate neurovascular coupling. Nature 2020, 579, 106–110. [Google Scholar] [CrossRef]
- Toth, P.; Tarantini, S.; Davila, A.; Valcarcel-Ares, M.N.; Tucsek, Z.; Varamini, B.; Ballabh, P.; Sonntag, W.E.; Baur, J.A.; Csiszar, A.; et al. Purinergic glio-endothelial coupling during neuronal activity: Role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex. Am. J. Physiol. Heart Circ. Physiol. 2015, 309, H1837–H1845. [Google Scholar] [CrossRef]
- Hopper, R.A.; Garthwaite, J. Tonic and phasic nitric oxide signals in hippocampal long-term potentiation. J. Neurosci. 2006, 26, 11513–11521. [Google Scholar] [CrossRef] [PubMed]
- Garthwaite, G.; Bartus, K.; Malcolm, D.; Goodwin, D.; Kollb-Sielecka, M.; Dooldeniya, C.; Garthwaite, J. Signaling from blood vessels to CNS axons through nitric oxide. J. Neurosci. 2006, 26, 7730–7740. [Google Scholar] [CrossRef]
- Garthwaite, J. Concepts of neural nitric oxide-mediated transmission. Eur. J. Neurosci. 2008, 27, 2783–2802. [Google Scholar] [CrossRef] [PubMed]
- Katusic, Z.S.; Austin, S.A. Endothelial nitric oxide: Protector of a healthy mind. Eur. Heart J. 2014, 35, 888–894. [Google Scholar] [CrossRef]
- Moore, C.I.; Cao, R. The hemo-neural hypothesis: On the role of blood flow in information processing. J. Neurophysiol. 2008, 99, 2035–2047. [Google Scholar] [CrossRef]
- Mishra, A. Binaural blood flow control by astrocytes: Listening to synapses and the vasculature. J. Physiol. 2017, 595, 1885–1902. [Google Scholar] [CrossRef]
- Presa, J.L.; Saravia, F.; Bagi, Z.; Filosa, J.A. Vasculo-Neuronal Coupling and Neurovascular Coupling at the Neurovascular Unit: Impact of Hypertension. Front. Physiol. 2020, 11, 584135. [Google Scholar] [CrossRef]
- Wang, F.; Cao, Y.; Ma, L.; Pei, H.; Rausch, W.D.; Li, H. Dysfunction of Cerebrovascular Endothelial Cells: Prelude to Vascular Dementia. Front. Aging Neurosci. 2018, 10, 376. [Google Scholar] [CrossRef]
- Blackshaw, S.; Eliasson, M.J.; Sawa, A.; Watkins, C.C.; Krug, D.; Gupta, A.; Arai, T.; Ferrante, R.J.; Snyder, S.H. Species, strain and developmental variations in hippocampal neuronal and endothelial nitric oxide synthase clarify discrepancies in nitric oxide-dependent synaptic plasticity. Neuroscience 2003, 119, 979–990. [Google Scholar] [CrossRef]
- Demas, G.E.; Kriegsfeld, L.J.; Blackshaw, S.; Huang, P.; Gammie, S.C.; Nelson, R.J.; Snyder, S.H. Elimination of aggressive behavior in male mice lacking endothelial nitric oxide synthase. J. Neurosci. 1999, 19, RC30. [Google Scholar] [CrossRef] [PubMed]
- Seidel, B.; Stanarius, A.; Wolf, G. Differential expression of neuronal and endothelial nitric oxide synthase in blood vessels of the rat brain. Neurosci. Lett. 1997, 239, 109–112. [Google Scholar] [CrossRef] [PubMed]
- Negri, S.; Faris, P.; Soda, T.; Moccia, F. Endothelial signaling at the core of neurovascular coupling: The emerging role of endothelial inward-rectifier K(+) (Kir2.1) channels and N-methyl-d-aspartate receptors in the regulation of cerebral blood flow. Int. J. Biochem. Cell Biol. 2021, 135, 105983. [Google Scholar] [CrossRef]
- Guerra, G.; Lucariello, A.; Perna, A.; Botta, L.; De Luca, A.; Moccia, F. The Role of Endothelial Ca2+ Signaling in Neurovascular Coupling: A View from the Lumen. Int. J. Mol. Sci. 2018, 19, 938. [Google Scholar] [CrossRef]
- Abbott, N.J.; Patabendige, A.A.; Dolman, D.E.; Yusof, S.R.; Begley, D.J. Structure and function of the blood-brain barrier. Neurobiol. Dis. 2010, 37, 13–25. [Google Scholar] [CrossRef]
- Hamel, E. Perivascular nerves and the regulation of cerebrovascular tone. J. Appl. Physiol. 2006, 100, 1059–1064. [Google Scholar] [CrossRef]
- Agarwal, N.; Carare, R.O. Cerebral Vessels: An Overview of Anatomy, Physiology, and Role in the Drainage of Fluids and Solutes. Front. Neurol. 2020, 11, 611485. [Google Scholar] [CrossRef]
- Garthwaite, J. From synaptically localized to volume transmission by nitric oxide. J. Physiol. 2016, 594, 9–18. [Google Scholar] [CrossRef]
- Garthwaite, J. Nitric oxide as a multimodal brain transmitter. Brain Neurosci. Adv. 2018, 2, 2398212818810683. [Google Scholar] [CrossRef] [PubMed]
- Lourenco, C.F.; Ledo, A.; Barbosa, R.M.; Laranjinha, J. Neurovascular-neuroenergetic coupling axis in the brain: Master regulation by nitric oxide and consequences in aging and neurodegeneration. Free Radic. Biol. Med. 2017, 108, 668–682. [Google Scholar] [CrossRef] [PubMed]
- Gotti, S.; Sica, M.; Viglietti-Panzica, C.; Panzica, G. Distribution of nitric oxide synthase immunoreactivity in the mouse brain. Microsc. Res. Tech. 2005, 68, 13–35. [Google Scholar] [CrossRef] [PubMed]
- Chachlaki, K.; Garthwaite, J.; Prevot, V. The gentle art of saying NO: How nitric oxide gets things done in the hypothalamus. Nat. Rev. Endocrinol. 2017, 13, 521–535. [Google Scholar] [CrossRef] [PubMed]
- Mapelli, L.; Gagliano, G.; Soda, T.; Laforenza, U.; Moccia, F.; D’Angelo, E.U. Granular Layer Neurons Control Cerebellar Neurovascular Coupling Through an NMDA Receptor/NO-Dependent System. J. Neurosci. 2017, 37, 1340–1351. [Google Scholar] [CrossRef] [PubMed]
- O’Dell, T.J.; Huang, P.L.; Dawson, T.M.; Dinerman, J.L.; Snyder, S.H.; Kandel, E.R.; Fishman, M.C. Endothelial NOS and the blockade of LTP by NOS inhibitors in mice lacking neuronal NOS. Science 1994, 265, 542–546. [Google Scholar] [CrossRef] [PubMed]
- Dinerman, J.L.; Dawson, T.M.; Schell, M.J.; Snowman, A.; Snyder, S.H. Endothelial nitric oxide synthase localized to hippocampal pyramidal cells: Implications for synaptic plasticity. Proc. Natl. Acad. Sci. USA 1994, 91, 4214–4218. [Google Scholar] [CrossRef] [PubMed]
- Doyle, C.A.; Slater, P. Localization of neuronal and endothelial nitric oxide synthase isoforms in human hippocampus. Neuroscience 1997, 76, 387–395. [Google Scholar] [CrossRef] [PubMed]
- Li, Q.; Chen, Y.; Li, B.; Luo, C.; Zuo, S.; Liu, X.; Zhang, J.H.; Ruan, H.; Feng, H. Hemoglobin induced NO/cGMP suppression Deteriorate Microcirculation via Pericyte Phenotype Transformation after Subarachnoid Hemorrhage in Rats. Sci. Rep. 2016, 6, 22070. [Google Scholar] [CrossRef]
- Longden, T.A.; Zhao, G.; Hariharan, A.; Lederer, W.J. Pericytes and the Control of Blood Flow in Brain and Heart. Annu. Rev. Physiol. 2023, 85, 137–164. [Google Scholar] [CrossRef] [PubMed]
- Moccia, F.; Brunetti, V.; Perna, A.; Guerra, G.; Soda, T.; Berra-Romani, R. The Molecular Heterogeneity of Store-Operated Ca2+ Entry in Vascular Endothelial Cells: The Different roles of Orai1 and TRPC1/TRPC4 Channels in the Transition from Ca2+-Selective to Non-Selective Cation Currents. Int. J. Mol. Sci. 2023, 24, 3259. [Google Scholar] [CrossRef]
- Moccia, F.; Brunetti, V.; Soda, T.; Berra-Romani, R.; Scarpellino, G. Cracking the Endothelial Calcium (Ca2+) Code: A Matter of Timing and Spacing. Int. J. Mol. Sci. 2023, 24, 16765. [Google Scholar] [CrossRef]
- Stobart, J.L.; Lu, L.; Anderson, H.D.; Mori, H.; Anderson, C.M. Astrocyte-induced cortical vasodilation is mediated by D-serine and endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 2013, 110, 3149–3154. [Google Scholar] [CrossRef] [PubMed]
- Hogan-Cann, A.D.; Lu, P.; Anderson, C.M. Endothelial NMDA receptors mediate activity-dependent brain hemodynamic responses in mice. Proc. Natl. Acad. Sci. USA 2019, 116, 10229–10231. [Google Scholar] [CrossRef]
- Negri, S.; Faris, P.; Maniezzi, C.; Pellavio, G.; Spaiardi, P.; Botta, L.; Laforenza, U.; Biella, G.; Moccia, D.F. NMDA receptors elicit flux-independent intracellular Ca2+ signals via metabotropic glutamate receptors and flux-dependent nitric oxide release in human brain microvascular endothelial cells. Cell Calcium. 2021, 99, 102454. [Google Scholar] [CrossRef]
- Blatter, L.A. Tissue Specificity: SOCE: Implications for Ca2+ Handling in Endothelial Cells. Adv. Exp. Med. Biol. 2017, 993, 343–361. [Google Scholar] [CrossRef] [PubMed]
- Longden, T.A.; Mughal, A.; Hennig, G.W.; Harraz, O.F.; Shui, B.; Lee, F.K.; Lee, J.C.; Reining, S.; Kotlikoff, M.I.; Konig, G.M.; et al. Local IP3 receptor-mediated Ca2+ signals compound to direct blood flow in brain capillaries. Sci. Adv. 2021, 7, eabh0101. [Google Scholar] [CrossRef]
- Moccia, F.; Negri, S.; Faris, P.; Angelone, T. Targeting endothelial ion signalling to rescue cerebral blood flow in cerebral disorders. Vascul. Pharmacol. 2022, 145, 106997. [Google Scholar] [CrossRef] [PubMed]
- Negri, S.; Faris, P.; Pellavio, G.; Botta, L.; Orgiu, M.; Forcaia, G.; Sancini, G.; Laforenza, U.; Moccia, F. Group 1 metabotropic glutamate receptors trigger glutamate-induced intracellular Ca2+ signals and nitric oxide release in human brain microvascular endothelial cells. Cell Mol. Life Sci. 2020, 77, 2235–2253. [Google Scholar] [CrossRef]
- Zuccolo, E.; Laforenza, U.; Negri, S.; Botta, L.; Berra-Romani, R.; Faris, P.; Scarpellino, G.; Forcaia, G.; Pellavio, G.; Sancini, G.; et al. Muscarinic M5 receptors trigger acetylcholine-induced Ca2+ signals and nitric oxide release in human brain microvascular endothelial cells. J. Cell. Physiol. 2019, 234, 4540–4562. [Google Scholar] [CrossRef]
- Negri, S.; Scolari, F.; Vismara, M.; Brunetti, V.; Faris, P.; Terribile, G.; Sancini, G.; Berra-Romani, R.; Moccia, F. GABA(A) and GABA(B) Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells. Cells 2022, 11, 3860. [Google Scholar] [CrossRef] [PubMed]
- Berra-Romani, R.; Brunetti, V.; Pellavio, G.; Soda, T.; Laforenza, U.; Scarpellino, G.; Moccia, F. Allyl Isothiocianate Induces Ca2+ Signals and Nitric Oxide Release by Inducing Reactive Oxygen Species Production in the Human Cerebrovascular Endothelial Cell Line hCMEC/D3. Cells 2023, 12, 1732. [Google Scholar] [CrossRef] [PubMed]
- Brailoiu, E.; Shipsky, M.M.; Yan, G.; Abood, M.E.; Brailoiu, G.C. Mechanisms of modulation of brain microvascular endothelial cells function by thrombin. Brain Res. 2017, 1657, 167–175. [Google Scholar] [CrossRef] [PubMed]
- Brailoiu, E.; Barlow, C.L.; Ramirez, S.H.; Abood, M.E.; Brailoiu, G.C. Effects of Platelet-Activating Factor on Brain Microvascular Endothelial Cells. Neuroscience 2018, 377, 105–113. [Google Scholar] [CrossRef] [PubMed]
- Harraz, O.F.; Klug, N.R.; Senatore, A.J.; Hill-Eubanks, D.C.; Nelson, M.T. Piezo1 Is a Mechanosensor Channel in Central Nervous System Capillaries. Circ. Res. 2022, 130, 1531–1546. [Google Scholar] [CrossRef] [PubMed]
- Lim, X.R.; Harraz, O.F. Mechanosensing by Vascular Endothelium. Annu. Rev. Physiol. 2024, 86, 71–97. [Google Scholar] [CrossRef] [PubMed]
- Garcia, V.; Sessa, W.C. Endothelial NOS: Perspective and recent developments. Br. J. Pharmacol. 2019, 176, 189–196. [Google Scholar] [CrossRef] [PubMed]
- Ching, L.C.; Kou, Y.R.; Shyue, S.K.; Su, K.H.; Wei, J.; Cheng, L.C.; Yu, Y.B.; Pan, C.C.; Lee, T.S. Molecular mechanisms of activation of endothelial nitric oxide synthase mediated by transient receptor potential vanilloid type 1. Cardiovasc. Res. 2011, 91, 492–501. [Google Scholar] [CrossRef] [PubMed]
- Lee, G.H.; Kim, C.Y.; Zheng, C.; Jin, S.W.; Kim, J.Y.; Lee, S.Y.; Kim, M.Y.; Han, E.H.; Hwang, Y.P.; Jeong, H.G. Rutaecarpine Increases Nitric Oxide Synthesis via eNOS Phosphorylation by TRPV1-Dependent CaMKII and CaMKKbeta/AMPK Signaling Pathway in Human Endothelial Cells. Int. J. Mol. Sci. 2021, 22, 9407. [Google Scholar] [CrossRef]
- Steinert, J.R.; Kopp-Scheinpflug, C.; Baker, C.; Challiss, R.A.; Mistry, R.; Haustein, M.D.; Griffin, S.J.; Tong, H.; Graham, B.P.; Forsythe, I.D. Nitric oxide is a volume transmitter regulating postsynaptic excitability at a glutamatergic synapse. Neuron 2008, 60, 642–656. [Google Scholar] [CrossRef] [PubMed]
- Ledo, A.; Barbosa, R.M.; Gerhardt, G.A.; Cadenas, E.; Laranjinha, J. Concentration dynamics of nitric oxide in rat hippocampal subregions evoked by stimulation of the NMDA glutamate receptor. Proc. Natl. Acad. Sci. USA 2005, 102, 17483–17488. [Google Scholar] [CrossRef] [PubMed]
- Lu, L.; Hogan-Cann, A.D.; Globa, A.K.; Lu, P.; Nagy, J.I.; Bamji, S.X.; Anderson, C.M. Astrocytes drive cortical vasodilatory signaling by activating endothelial NMDA receptors. J. Cereb. Blood Flow Metab. 2019, 39, 481–496. [Google Scholar] [CrossRef]
- Garthwaite, J.; Charles, S.L.; Chess-Williams, R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 1988, 336, 385–388. [Google Scholar] [CrossRef] [PubMed]
- Wilson, C.; Saunter, C.D.; Girkin, J.M.; McCarron, J.G. Clusters of specialized detector cells provide sensitive and high fidelity receptor signaling in the intact endothelium. FASEB J. 2016, 30, 2000–2013. [Google Scholar] [CrossRef]
- Lee, M.D.; Wilson, C.; Saunter, C.D.; Kennedy, C.; Girkin, J.M.; McCarron, J.G. Spatially structured cell populations process multiple sensory signals in parallel in intact vascular endothelium. Sci. Signal. 2018, 11, eaar4411. [Google Scholar] [CrossRef] [PubMed]
- Lee, M.D.; Buckley, C.; Zhang, X.; Louhivuori, L.; Uhlen, P.; Wilson, C.; McCarron, J.G. Small-world connectivity dictates collective endothelial cell signaling. Proc. Natl. Acad. Sci. USA 2022, 119, e2118927119. [Google Scholar] [CrossRef]
- Zambach, S.A.; Cai, C.; Helms, H.C.C.; Hald, B.O.; Dong, Y.; Fordsmann, J.C.; Nielsen, R.M.; Hu, J.; Lonstrup, M.; Brodin, B.; et al. Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion. Proc. Natl. Acad. Sci. USA 2021, 118, e2023749118. [Google Scholar] [CrossRef]
- Andrabi, S.M.; Sharma, N.S.; Karan, A.; Shahriar, S.M.S.; Cordon, B.; Ma, B.; Xie, J. Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications. Adv. Sci. 2023, 10, e2303259. [Google Scholar] [CrossRef]
- Martinez-Ruiz, A.; Cadenas, S.; Lamas, S. Nitric oxide signaling: Classical, less classical, and nonclassical mechanisms. Free Radic. Biol. Med. 2011, 51, 17–29. [Google Scholar] [CrossRef]
- Atochin, D.N.; Demchenko, I.T.; Astern, J.; Boso, A.E.; Piantadosi, C.A.; Huang, P.L. Contributions of endothelial and neuronal nitric oxide synthases to cerebrovascular responses to hyperoxia. J. Cereb. Blood Flow Metab. 2003, 23, 1219–1226. [Google Scholar] [CrossRef]
- Yamada, M.; Lamping, K.G.; Duttaroy, A.; Zhang, W.; Cui, Y.; Bymaster, F.P.; McKinzie, D.L.; Felder, C.C.; Deng, C.X.; Faraci, F.M.; et al. Cholinergic dilation of cerebral blood vessels is abolished in M(5) muscarinic acetylcholine receptor knockout mice. Proc. Natl. Acad. Sci. USA 2001, 98, 14096–14101. [Google Scholar] [CrossRef] [PubMed]
- Araya, R.; Noguchi, T.; Yuhki, M.; Kitamura, N.; Higuchi, M.; Saido, T.C.; Seki, K.; Itohara, S.; Kawano, M.; Tanemura, K.; et al. Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice. Neurobiol. Dis. 2006, 24, 334–344. [Google Scholar] [CrossRef] [PubMed]
- Bintig, W.; Begandt, D.; Schlingmann, B.; Gerhard, L.; Pangalos, M.; Dreyer, L.; Hohnjec, N.; Couraud, P.O.; Romero, I.A.; Weksler, B.B.; et al. Purine receptors and Ca2+ signalling in the human blood-brain barrier endothelial cell line hCMEC/D3. Purinergic Signal. 2012, 8, 71–80. [Google Scholar] [CrossRef] [PubMed]
- Hogan-Cann, A.D.; Anderson, C.M. Physiological Roles of Non-Neuronal NMDA Receptors. Trends Pharmacol. Sci. 2016, 37, 750–767. [Google Scholar] [CrossRef] [PubMed]
- Brunetti, V.; Soda, T.; Berra-Romani, R.; De Sarro, G.; Guerra, G.; Scarpellino, G.; Moccia, F. Two Signaling Modes Are Better than One: Flux-Independent Signaling by Ionotropic Glutamate Receptors Is Coming of Age. Biomedicines 2024, 12, 880. [Google Scholar] [CrossRef] [PubMed]
- LeMaistre, J.L.; Sanders, S.A.; Stobart, M.J.; Lu, L.; Knox, J.D.; Anderson, H.D.; Anderson, C.M. Coactivation of NMDA receptors by glutamate and D-serine induces dilation of isolated middle cerebral arteries. J. Cereb. Blood Flow Metab. 2012, 32, 537–547. [Google Scholar] [CrossRef] [PubMed]
- Nippert, A.R.; Biesecker, K.R.; Newman, E.A. Mechanisms Mediating Functional Hyperemia in the Brain. Neuroscientist 2018, 24, 73–83. [Google Scholar] [CrossRef] [PubMed]
- O’Gallagher, K.; Puledda, F.; O’Daly, O.; Ryan, M.; Dancy, L.; Chowienczyk, P.J.; Zelaya, F.; Goadsby, P.J.; Shah, A.M. Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans. Cardiovasc. Res. 2022, 118, 1321–1329. [Google Scholar] [CrossRef] [PubMed]
- Hoiland, R.L.; Caldwell, H.G.; Howe, C.A.; Nowak-Fluck, D.; Stacey, B.S.; Bailey, D.M.; Paton, J.F.R.; Green, D.J.; Sekhon, M.S.; Macleod, D.B.; et al. Nitric oxide is fundamental to neurovascular coupling in humans. J. Physiol. 2020, 598, 4927–4939. [Google Scholar] [CrossRef] [PubMed]
- Rocha, M.P.; Caldwell, H.G.; Gliemann, L. How do we kNOw the individual contribution of eNOS and nNOS for cerebral blood flow regulation? J. Physiol. 2022, 600, 3–4. [Google Scholar] [CrossRef] [PubMed]
- Liao, F.F.; Lin, G.; Chen, X.; Chen, L.; Zheng, W.; Raghow, R.; Zhou, F.M.; Shih, A.Y.; Tan, X.L. Endothelial Nitric Oxide Synthase-Deficient Mice: A Model of Spontaneous Cerebral Small-Vessel Disease. Am. J. Pathol. 2021, 191, 1932–1945. [Google Scholar] [CrossRef] [PubMed]
- Hariharan, A.; Jing, Y.; Collie, N.D.; Zhang, H.; Liu, P. Altered neurovascular coupling and brain arginine metabolism in endothelial nitric oxide synthase deficient mice. Nitric Oxide 2019, 87, 60–72. [Google Scholar] [CrossRef]
- Atochin, D.N.; Huang, P.L. Endothelial nitric oxide synthase transgenic models of endothelial dysfunction. Pflugers Arch. 2010, 460, 965–974. [Google Scholar] [CrossRef] [PubMed]
- Huang, P.L.; Huang, Z.; Mashimo, H.; Bloch, K.D.; Moskowitz, M.A.; Bevan, J.A.; Fishman, M.C. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995, 377, 239–242. [Google Scholar] [CrossRef] [PubMed]
- Shesely, E.G.; Maeda, N.; Kim, H.S.; Desai, K.M.; Krege, J.H.; Laubach, V.E.; Sherman, P.A.; Sessa, W.C.; Smithies, O. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 1996, 93, 13176–13181. [Google Scholar] [CrossRef]
- Cui, X.; Chopp, M.; Zacharek, A.; Zhang, C.; Roberts, C.; Chen, J. Role of endothelial nitric oxide synthetase in arteriogenesis after stroke in mice. Neuroscience 2009, 159, 744–750. [Google Scholar] [CrossRef]
- Song, J.; Kim, O.J.; Kim, H.S.; Bae, S.J.; Hong, S.P.; Oh, D.; Kim, N.K. Endothelial nitric oxide synthase gene polymorphisms and the risk of silent brain infarction. Int. J. Mol. Med. 2010, 25, 819–823. [Google Scholar] [CrossRef]
- Hassan, A.; Gormley, K.; O’Sullivan, M.; Knight, J.; Sham, P.; Vallance, P.; Bamford, J.; Markus, H. Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease. Stroke 2004, 35, 654–659. [Google Scholar] [CrossRef]
- Jackson, W.F. Calcium-Dependent Ion Channels and the Regulation of Arteriolar Myogenic Tone. Front. Physiol. 2021, 12, 770450. [Google Scholar] [CrossRef]
- Jackson, W.F. Endothelial Ion Channels and Cell-Cell Communication in the Microcirculation. Front. Physiol. 2022, 13, 805149. [Google Scholar] [CrossRef]
- Longden, T.A.; Dabertrand, F.; Koide, M.; Gonzales, A.L.; Tykocki, N.R.; Brayden, J.E.; Hill-Eubanks, D.; Nelson, M.T. Capillary K(+)-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Nat. Neurosci. 2017, 20, 717–726. [Google Scholar] [CrossRef]
- Harraz, O.F.; Longden, T.A.; Dabertrand, F.; Hill-Eubanks, D.; Nelson, M.T. Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion. Proc. Natl. Acad. Sci. USA 2018, 115, E3569–E3577. [Google Scholar] [CrossRef] [PubMed]
- Sancho, M.; Klug, N.R.; Mughal, A.; Koide, M.; Huerta de la Cruz, S.; Heppner, T.J.; Bonev, A.D.; Hill-Eubanks, D.; Nelson, M.T. Adenosine signaling activates ATP-sensitive K(+) channels in endothelial cells and pericytes in CNS capillaries. Sci. Signal. 2022, 15, eabl5405. [Google Scholar] [CrossRef]
- Thakore, P.; Alvarado, M.G.; Ali, S.; Mughal, A.; Pires, P.W.; Yamasaki, E.; Pritchard, H.A.; Isakson, B.E.; Tran, C.H.T.; Earley, S. Brain endothelial cell TRPA1 channels initiate neurovascular coupling. eLife 2021, 10, e63040. [Google Scholar] [CrossRef]
- Garthwaite, J. NO as a multimodal transmitter in the brain: Discovery and current status. Br. J. Pharmacol. 2019, 176, 197–211. [Google Scholar] [CrossRef]
- Hardingham, N.; Dachtler, J.; Fox, K. The role of nitric oxide in pre-synaptic plasticity and homeostasis. Front. Cell. Neurosci. 2013, 7, 190. [Google Scholar] [CrossRef]
- Kantor, D.B.; Lanzrein, M.; Stary, S.J.; Sandoval, G.M.; Smith, W.B.; Sullivan, B.M.; Davidson, N.; Schuman, E.M. A role for endothelial NO synthase in LTP revealed by adenovirus-mediated inhibition and rescue. Science 1996, 274, 1744–1748. [Google Scholar] [CrossRef]
- Wilson, R.I.; Yanovsky, J.; Godecke, A.; Stevens, D.R.; Schrader, J.; Haas, H.L. Endothelial nitric oxide synthase and LTP. Nature 1997, 386, 338. [Google Scholar] [CrossRef] [PubMed]
- Son, H.; Hawkins, R.D.; Martin, K.; Kiebler, M.; Huang, P.L.; Fishman, M.C.; Kandel, E.R. Long-term potentiation is reduced in mice that are doubly mutant in endothelial and neuronal nitric oxide synthase. Cell 1996, 87, 1015–1023. [Google Scholar] [CrossRef] [PubMed]
- Haul, S.; Godecke, A.; Schrader, J.; Haas, H.L.; Luhmann, H.J. Impairment of neocortical long-term potentiation in mice deficient of endothelial nitric oxide synthase. J. Neurophysiol. 1999, 81, 494–497. [Google Scholar] [CrossRef]
- Doreulee, N.; Sergeeva, O.A.; Yanovsky, Y.; Chepkova, A.N.; Selbach, O.; Godecke, A.; Schrader, J.; Haas, H.L. Cortico-striatal synaptic plasticity in endothelial nitric oxide synthase deficient mice. Brain Res. 2003, 964, 159–163. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.Y.; Takagi, H.; Stoney, P.N.; Echeverria, A.; Kuhn, B.; Hsu, K.S.; Takahashi, T. Anoxia-induced hippocampal LTP is regeneratively produced by glutamate and nitric oxide from the neuro-glial-endothelial axis. iScience 2024, 27, 109515. [Google Scholar] [CrossRef] [PubMed]
- Yang, M.; Sun, D.; Wang, Y.; Yan, M.; Zheng, J.; Ren, J. Cognitive Impairment in Heart Failure: Landscape, Challenges, and Future Directions. Front. Cardiovasc. Med. 2021, 8, 831734. [Google Scholar] [CrossRef]
- Liu, J.; Xiao, G.; Liang, Y.; He, S.; Lyu, M.; Zhu, Y. Heart-brain interaction in cardiogenic dementia: Pathophysiology and therapeutic potential. Front. Cardiovasc. Med. 2024, 11, 1304864. [Google Scholar] [CrossRef]
- Iadecola, C.; Gottesman, R.F. Neurovascular and Cognitive Dysfunction in Hypertension. Circ. Res. 2019, 124, 1025–1044. [Google Scholar] [CrossRef] [PubMed]
- Selkoe, D.J. The molecular pathology of Alzheimer’s disease. Neuron 1991, 6, 487–498. [Google Scholar] [CrossRef] [PubMed]
- Hardy, J.A.; Higgins, G.A. Alzheimer’s disease: The amyloid cascade hypothesis. Science 1992, 256, 184–185. [Google Scholar] [CrossRef] [PubMed]
- Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat. Rev. Neurosci. 2004, 5, 347–360. [Google Scholar] [CrossRef] [PubMed]
- Iadecola, C.; Duering, M.; Hachinski, V.; Joutel, A.; Pendlebury, S.T.; Schneider, J.A.; Dichgans, M. Vascular Cognitive Impairment and Dementia: JACC Scientific Expert Panel. J. Am. Coll. Cardiol. 2019, 73, 3326–3344. [Google Scholar] [CrossRef] [PubMed]
- Iadecola, C. The pathobiology of vascular dementia. Neuron 2013, 80, 844–866. [Google Scholar] [CrossRef] [PubMed]
- Austin, S.A.; Santhanam, A.V.; Hinton, D.J.; Choi, D.S.; Katusic, Z.S. Endothelial nitric oxide deficiency promotes Alzheimer’s disease pathology. J. Neurochem. 2013, 127, 691–700. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.; Jiang, X.; Ma, L.; Wei, W.; Li, Z.; Chang, S.; Wen, J.; Sun, J.; Li, H. Role of Abeta in Alzheimer’s-related synaptic dysfunction. Front. Cell Dev. Biol. 2022, 10, 964075. [Google Scholar] [CrossRef]
- An, L.; Shen, Y.; Chopp, M.; Zacharek, A.; Venkat, P.; Chen, Z.; Li, W.; Qian, Y.; Landschoot-Ward, J.; Chen, J. Deficiency of Endothelial Nitric Oxide Synthase (eNOS) Exacerbates Brain Damage and Cognitive Deficit in A Mouse Model of Vascular Dementia. Aging Dis. 2021, 12, 732–746. [Google Scholar] [CrossRef] [PubMed]
- Ahmed, S.; Jing, Y.; Mockett, B.G.; Zhang, H.; Abraham, W.C.; Liu, P. Partial Endothelial Nitric Oxide Synthase Deficiency Exacerbates Cognitive Deficit and Amyloid Pathology in the APPswe/PS1DeltaE9 Mouse Model of Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 23, 7316. [Google Scholar] [CrossRef]
- Li, S.; Wang, Y.; Jiang, Z.; Huai, Y.; Liao, J.K.; Lynch, K.A.; Zafonte, R.; Wood, L.J.; Wang, Q.M. Impaired Cognitive Performance in Endothelial Nitric Oxide Synthase Knockout Mice After Ischemic Stroke: A Pilot Study. Am. J. Phys. Med. Rehabil. 2018, 97, 492–499. [Google Scholar] [CrossRef] [PubMed]
- Kim, K.J.; Iddings, J.A.; Stern, J.E.; Blanco, V.M.; Croom, D.; Kirov, S.A.; Filosa, J.A. Astrocyte contributions to flow/pressure-evoked parenchymal arteriole vasoconstriction. J. Neurosci. 2015, 35, 8245–8257. [Google Scholar] [CrossRef] [PubMed]
- Kim, K.J.; Ramiro Diaz, J.; Iddings, J.A.; Filosa, J.A. Vasculo-Neuronal Coupling: Retrograde Vascular Communication to Brain Neurons. J. Neurosci. 2016, 36, 12624–12639. [Google Scholar] [CrossRef] [PubMed]
- Zhou, S.; Giannetto, M.; DeCourcey, J.; Kang, H.; Kang, N.; Li, Y.; Zheng, S.; Zhao, H.; Simmons, W.R.; Wei, H.S.; et al. Oxygen tension-mediated erythrocyte membrane interactions regulate cerebral capillary hyperemia. Sci. Adv. 2019, 5, eaaw4466. [Google Scholar] [CrossRef] [PubMed]
- Rungta, R.L.; Chaigneau, E.; Osmanski, B.F.; Charpak, S. Vascular Compartmentalization of Functional Hyperemia from the Synapse to the Pia. Neuron 2018, 99, 362–375.e4. [Google Scholar] [CrossRef] [PubMed]
- Shi, Y.; Liu, X.; Gebremedhin, D.; Falck, J.R.; Harder, D.R.; Koehler, R.C. Interaction of mechanisms involving epoxyeicosatrienoic acids, adenosine receptors, and metabotropic glutamate receptors in neurovascular coupling in rat whisker barrel cortex. J. Cereb. Blood Flow Metab. 2008, 28, 111–125. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.; Li, C.; Falck, J.R.; Roman, R.J.; Harder, D.R.; Koehler, R.C. Interaction of nitric oxide, 20-HETE, and EETs during functional hyperemia in whisker barrel cortex. Am. J. Physiol. Heart Circ. Physiol. 2008, 295, H619–H631. [Google Scholar] [CrossRef] [PubMed]
- Tran, C.H.T.; Peringod, G.; Gordon, G.R. Astrocytes Integrate Behavioral State and Vascular Signals during Functional Hyperemia. Neuron 2018, 100, 1133–1148.e3. [Google Scholar] [CrossRef] [PubMed]
- Yemisci, M.; Gursoy-Ozdemir, Y.; Vural, A.; Can, A.; Topalkara, K.; Dalkara, T. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat. Med. 2009, 15, 1031–1037. [Google Scholar] [CrossRef] [PubMed]
- Nelissen, E.; Schepers, M.; Ponsaerts, L.; Foulquier, S.; Bronckaers, A.; Vanmierlo, T.; Sandner, P.; Prickaerts, J. Soluble guanylyl cyclase: A novel target for the treatment of vascular cognitive impairment? Pharmacol. Res. 2023, 197, 106970. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Scarpellino, G.; Brunetti, V.; Berra-Romani, R.; De Sarro, G.; Guerra, G.; Soda, T.; Moccia, F. The Unexpected Role of the Endothelial Nitric Oxide Synthase at the Neurovascular Unit: Beyond the Regulation of Cerebral Blood Flow. Int. J. Mol. Sci. 2024, 25, 9071. https://doi.org/10.3390/ijms25169071
Scarpellino G, Brunetti V, Berra-Romani R, De Sarro G, Guerra G, Soda T, Moccia F. The Unexpected Role of the Endothelial Nitric Oxide Synthase at the Neurovascular Unit: Beyond the Regulation of Cerebral Blood Flow. International Journal of Molecular Sciences. 2024; 25(16):9071. https://doi.org/10.3390/ijms25169071
Chicago/Turabian StyleScarpellino, Giorgia, Valentina Brunetti, Roberto Berra-Romani, Giovambattista De Sarro, Germano Guerra, Teresa Soda, and Francesco Moccia. 2024. "The Unexpected Role of the Endothelial Nitric Oxide Synthase at the Neurovascular Unit: Beyond the Regulation of Cerebral Blood Flow" International Journal of Molecular Sciences 25, no. 16: 9071. https://doi.org/10.3390/ijms25169071