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1. Hyperacute pathophysiology of traumatic and vascular brain injury captured by ultrasound, photoacoustic, and magnetic resonance imaging

Author

Kamali, Ali, Dieckhaus, Laurel, Peters, Emily C., Preszler, Collin A., Witte, Russel S., Pires, Paulo W., Hutchinson, Elizabeth B., and Laksari, Kaveh

Subjects
Quantitative Biology - Quantitative Methods, Quantitative Biology - Tissues and Organs
Abstract

Cerebrovascular dynamics and pathomechanisms that evolve in the minutes and hours following traumatic vascular injury in the brain remain largely unknown. We investigated the pathophysiology evolution within the first three hours after closed-head traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH), two common traumatic vascular injuries, in mice. We took a multi-modal imaging approach using photoacoustic, color Doppler, and magnetic resonance imaging (MRI) in mice. Brain oxygenation (%sO2) and velocity-weighted volume of blood flow (VVF) values significantly decreased from baseline to fifteen minutes after both TBI and SAH. TBI resulted in 19.2% and 41.0% ipsilateral %sO2 and VVF reductions 15 minutes post injury while SAH resulted in 43.9% %sO2 and 85.0% VVF reduction ipsilaterally (p<0.001). We found partial recovery of %sO2 from 15 minutes to 3-hours after injury for TBI but not SAH. Hemorrhage, edema, reduced perfusion, and altered diffusivity were evident from MRI scans acquired 90-150 minutes after injury in both models although the spatial distribution was mostly focal for TBI and diffuse for SAH. The results reveal that the cerebral %sO2 deficits immediately following injuries are reversible for TBI and irreversible for SAH. Our findings can inform future studies on mitigating these early responses to improve long-term recovery., Comment: Update in order of figure panels for Figure 3

Published
2022

3. Theoretical Models of Neurovascular Coupling: Role of Potassium Ions

Author

Pires, Paulo W., Fuglevand, Andrew J., Eggers, Erika D., Djurich, Sara, Pires, Paulo W., Fuglevand, Andrew J., Eggers, Erika D., and Djurich, Sara

Abstract

The brain is a highly energetic organ that lacks an energy storage system and is dependent on continuous blood flow to provide oxygen and other nutrients needed for normal function. Local blood flow increases in response to neuronal activity, a phenomenon known as neurovascular coupling (NVC). In this response, active neurons send a signal to local capillaries, which in turn send a signal to upstream arterioles. The arterioles then dilate and increase blood flow specifically to the active area. While NVC has been studied extensively and multiple mechanisms have been proposed, the mechanisms regulating NVC remain incompletely understood. One potential mechanism is the diffusion of potassium ions released by neurons during activity through the extracellular space (ECS) to the capillaries. Changes in extracellular potassium concentration have been shown to cause changes in inward-rectifying potassium (KIR) channel conductance. As extracellular potassium concentration increases, KIR channel conductance increases, causing hyperpolarization of endothelial cells. The change in membrane potential can passively spread through the endothelial cells to arterioles via gap junctions in what is known as a conducted response. Testing this hypothesized mechanism experimentally with quantifiable results is technically difficult, due to the need to measure potassium concentrations in the ECS with high spatial and temporal resolution.Mathematical modeling of the proposed mechanism provides a means to predict changes in potassium concentration and membrane potentials with position and time, and thereby to test this hypothesis. To this end, mathematical models were created to analyze (i) changes in potassium concentration due to uptake and release of potassium by cells in the brain; (ii) the time course of diffusion of potassium in the ECS, including effects due to electrodiffusion; (iii) how geometry of brain microanatomy affects the rate of diffusion and maximum potassium concentratio

Published
2024

5. PNA5, A Novel Mas Receptor Agonist, Improves Neurovascular and Blood-Brain-Barrier Function in a Mouse Model of Vascular Cognitive Impairment and Dementia.

Author

Hoyer-Kimura, Christina, Hay, Meredith, Konhilas, John P., Morrison, Helena W, Methajit, Methawasin, Strom, Joshua, Polt, Robin, Salcedo, Victoria, Fricks, Joshua P., Kalya, Anjna, and Pires, Paulo W.

Subjects
VASCULAR dementia, BLOOD-brain barrier, COGNITION disorders
Abstract

It is well established that decreased brain blood flow, increased reactive oxygen species production (ROS), and pro-inflammatory mechanisms accelerate neurodegenerative disease progressions, including vascular cognitive impairment and dementia (VCID). Previous studies in our laboratory have shown that our novel glycosylated Angiotensin-(1-7) Mas receptor agonist PNA5 reverses cognitive deficits, decreases ROS production, and inhibits inflammatory cytokine production in our preclinical mouse model of VCID that is induced by chronic heart failure (VCID-HF). In the present study, the effects of VCID-HF and treatment with PNA5 on microglia activation, blood-brain-barrier (BBB) integrity, and neurovascular coupling were assessed in our mouse model of VCID-HF. Three-month-old male C57BL/6J mice were subjected to myocardial infarction (MI) to induce heart failure for four weeks and then treated with subcutaneous injections of extended-release PNA5. Microglia activation, BBB permeability, cerebral perfusion, and neurovascular coupling were assessed. Results show that in our VCID-HF model, there was an increase in microglial activation and recruitment within the CA1 and CA3 regions of the hippocampus, a disruption in BBB integrity, and a decrease in neurovascular coupling. Treatment with PNA5 reversed these neuropathological effects of VCID-HF, suggesting that PNA5 may be an effective disease-modifying therapy to treat and prevent VCID. This study identifies potential mechanisms by which heart failure may induce VCID and highlights the possible mechanisms by which treatment with our novel glycosylated Angiotensin-(1-7) Mas receptor agonist, PNA5, may protect cognitive function in our model of VCID. [ABSTRACT FROM AUTHOR]

Published
2024
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8. Ebbs and tides of endothelial K+ currents that regulate blood flow.

Author

Martin, Paige E. and Pires, Paulo W.

Subjects
*CEREBRAL small vessel diseases, *VASCULAR smooth muscle, *BLOOD pressure, *DIASTOLIC blood pressure, *ALZHEIMER'S disease, *ENDOTHELIUM diseases, *HYPERTENSIVE crisis
Abstract

The article discusses the impact of hypertension on endothelial dysfunction and its role in regulating blood flow. It highlights the importance of KIR2.1 channels in promoting flow-induced vasodilation and the impairment of these channels in hypertensive arteries. The study by Do Couto et al. demonstrates that recovering KIR2.1 function could improve endothelial response to shear stress in hypertensive vessels, potentially leading to reduced blood pressure and hypertensive end-organ damage. Further research is needed to explore the mechanisms underlying KIR2.1 dysfunction in hypertension and its potential implications for vascular health. [Extracted from the article]

Published
2024
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13. BK (Ca) nitrosylation is associated with cerebral microvascular dysfunction in female 5x-FAD mice

Author

Silva, Josiane F., Polk, Felipe D., Savu, Andrea, Kath, Allison M., Gee, Michael T., and Pires, Paulo W.

Subjects
Article
Abstract

Cerebral microvascular dysfunction and nitro-oxidative stress are present in patients with Alzheimer’s disease (AD) and may contribute to disease progression and severity. Large conductance Ca (2+) -activated K (+) channels (BK (Ca) ) play an essential role in vasodilatory responses and maintenance of myogenic tone in resistance arteries. BK (Ca) can be modified in a pro-nitro-oxidative environment, resulting in decreased activity and vascular hyper-contractility, which can compromise cerebral blood flow regulation. We hypothesized that reductions in BK (Ca) function in cerebral arteries, as a consequence of nitro-oxidative stress, are associated with blunted neurovascular responses in the 5x-FAD model of AD. Using pressure myography, we observed that posterior communicating arteries (PComA) from 5 months-old female 5x-FAD mice showed higher spontaneous myogenic tone than wild-type (WT) littermates. Constriction to the BK (Ca) blocker iberiotoxin (30 nM) was smaller in 5x-FAD than WT, suggesting lower basal BK (Ca) activity, which was independent of alterations in intracellular Ca (2+) transients or BK (Ca) mRNA expression. These vascular changes were associated with higher levels of oxidative stress in female 5x-FAD and a higher level of S-nitrosylation in the BK (Ca) α-subunit. In females, pre-incubation of PComA from 5x-FAD with the reducing agent DTT (10 µM) rescued iberiotoxin-induced contraction. Female 5x-FAD mice showed increased expression of iNOS mRNA, lower resting cortical perfusion atop the frontal cortex, and impaired neurovascular coupling responses. No significant differences between male 5x-FAD and WT were observed for all parameters above. These data suggest that the exacerbation in BK (Ca) S-nitrosylation contributes to cerebrovascular and neurovascular impairments in female 5x-FAD mice. SIGNIFICANCE STATEMENT: Cerebral vascular dysfunction is increasingly recognized as a hallmark of Alzheimer’s disease and other dementias. Impaired microvascular regulation can lead to deficits in blood flow to the brain. An intrinsic property of the resistance vasculature is to constrict when pressurized (myogenic tone), generating a vasodilatory reserve. Detrimental over-constriction is prevented by vascular feedback mechanisms, including the opening of large-conductance Ca (2+) -activated K (+) channels (BK (Ca) ). Here, using a combination of molecular biology tools with ex vivo and in vivo vascular assessments, we show a novel mechanism associated with BK (Ca) dysfunction in the cerebral microvasculature of female 5x-FAD mice. We report increased BK (Ca) S-nitrosylation linked to reduced activity and, consequently, higher basal myogenic tone. These changes were associated with lower perfusion of the frontal cortex and impaired neurovascular reactivity, suggesting that nitro-oxidative stress is an important mechanism of vascular dysfunction in Alzheimer’s disease.

Published
2023

15. PNA5: A Novel Therapy for Heart Failure Induced Vascular Dementia

Author

Hay, Meredith, Pires, Paulo W., Duca, Frank, Hoyer-Kimura, Christina Helen, Hay, Meredith, Pires, Paulo W., Duca, Frank, and Hoyer-Kimura, Christina Helen

Abstract

Decreased brain blood flow, increased reactive oxygen species production (ROS), and pro-inflammatory mechanisms contribute to cognitive impairment and neurodegenerative disease progress, including vascular contributions to cognitive impairment and dementia (VCID). However, the specific mechanisms that underlie heart failure (HF)-induced VCID are not clearly elucidated. Hence, in this work of experiments to identify biomarkers and test PNA5 treatment in HF-induced VCID, we also needed to establish the mechanisms for HF-induced VCID as a unique disease model that in itself is able to be identified and treated.This present study aims to 1) establish the pathophysiology associated with the progression/development of HF-induced VCID and establish biomarkers to predict HF individuals at risk for developing VCID and 2) advance our novel pluripotent peptide, PNA5. We hypothesize that 1) PNA5 will improve cognitive outcomes in HF-induced VCID via neuroprotective effects by decreasing neuronal damage, inflammation, blood-brain barrier (BBB) permeability, and neurovascular coupling (NVC) function, and 2) that NfL is a biomarker for cognitive impairment in HF individuals and that NfL will increase with increased cognitive impairment as HF severity progresses. To answer our hypothesis, we measured PNA5 neuroprotective effects in our HF-induced VCID mouse model. VCID was induced via myocardial infarction (MI). Mice were treated for 24 days with subcutaneous injections of PNA5 (500 mcg/kg/day or 50 mcg/kg/day) or saline (as control) five weeks after the MI. Cognitive function was assessed following the treatment protocol, and NVC was analyzed. NfL and cytokine levels were measured from blood collected at death. Brains were either homogenized to analyze brain cytokine levels or total hemisphere BBB permeability or sectioned and stained to analyze microglia morphology and regional BBB permeability. Biomarkers in the clinical studies, including NfL and pTau181, were measured from ind

Published
2023

22. Contributors

Author

Acharya, Tusar Kanta, Ahern, Gerard P., Al-Omari, Ammar, Ann, Jihyae, Aswin, Tanishaa, Banerjee, Anushka, Behrendt, Marc, Belvisi, Maria G., Bencze, Noémi, Bevan, Stuart, Bishnoi, Mahendra, Blumberg, Peter M., Bonvini, Sara J., Brain, Susan D., Campbell, James N., Cantero, María del Rocío, Cantiello, Horacio F., Chapman, Hugh, Charrua, A., Chung, Man-Kyo, Connolly, James, Cruz, F., Das, Nilesh Kumar, De Logu, Francesco, Dubey, Nishant Kumar, Erin, Nuray, Fallah, Hamideh P., Geppetti, Pierangelo, Goswami, Luna, Goswami, Chandan, Halder, Ramizur Rahaman, He, Qian, Helyes, Zsuzsanna, Holm, Patrik, Huang, Huizhen, Hudhud, Lina, Iannone, Luigi Francesco, Islas, Leon D., Jaffal, Sahar Majdi, Jalava, Niina, Kashio, Makiko, Kiselyov, Kirill, Koivisto, Ari, Konkoly, János, Kormos, Viktória, Kovács-Rozmer, Katalin, Kriszta, Gábor, Kuhad, Anurag, Kumar, Shamit, Kumar, Vikash, Kumar, Satish, Kumar, Abhishek, Lal, Roshan, Leavell, Yaowaree, Lee, Jeewoo, Liang, Dong, Liu, Yusheng, Lopez, Kyle E., Lyu, Yihan, Mahapatra, Parnasree, McKemy, David D., Mishra, Subham, Mohanta, Sushama, Nadezhdin, Kirill D., Nassini, Romina, Oláh, Attila, Patel, Mihir, Pepelyayeva, Yuliya, Pertovaara, Antti, Phan, Thieu X., Pintér, Erika, Pires, Paulo W., Pohóczky, Krisztina, Porszász, Robert, Pozsgai, Gábor, Puri, Priyanka, Rangel-Yescas, Gisela E., Rantanen, Marja, Rardin, Benjamin, Rokade, Tejas Pravin, Rosenberg, Paul, Ross, Sarah E., Royal, Mike A., Sahu, Ram Prasad, Savu, Andrea, Shikha, Deep, Silva, Josiane F., Simpson, David, Sing, Raima, Snyder, Lindsey M., Sobolevsky, Alexander I., Sodhi, Rupinder Kaur, Stevens, Randall, Szallasi, Arpad, Szőke, Éva, Szöllősi, Attila Gábor, Tóth, Attila, Tóth, Balázs István, Van Horn, Wade D., Wang, Hongmei, Wortley, Michael A., Zhang, Jinwei, and Zhou, Zirui

Published
2024
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23. sj-pdf-2-jcb-10.1177_0271678X211039592 - Supplemental material for Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries

Author

Peters, Emily C, Gee, Michael T, Pawlowski, Lukas N, Kath, Allison M, Polk, Felipe D, Vance, Christopher J, Sacoman, Juliana L, and Pires, Paulo W

Subjects
110320 Radiology and Organ Imaging, FOS: Clinical medicine, FOS: Biological sciences, Medicine, Cell Biology, 110305 Emergency Medicine, 110306 Endocrinology, Biochemistry, 69999 Biological Sciences not elsewhere classified, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, sj-pdf-2-jcb-10.1177_0271678X211039592 for Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries by Emily C Peters, Michael T Gee, Lukas N Pawlowski, Allison M Kath, Felipe D Polk, Christopher J Vance, Juliana L Sacoman and Paulo W Pires in Journal of Cerebral Blood Flow & Metabolism

Published
2021
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24. sj-pdf-1-jcb-10.1177_0271678X211039592 - Supplemental material for Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries

Author

Peters, Emily C, Gee, Michael T, Pawlowski, Lukas N, Kath, Allison M, Polk, Felipe D, Vance, Christopher J, Sacoman, Juliana L, and Pires, Paulo W

Subjects
110320 Radiology and Organ Imaging, FOS: Clinical medicine, FOS: Biological sciences, Medicine, Cell Biology, 110305 Emergency Medicine, 110306 Endocrinology, Biochemistry, 69999 Biological Sciences not elsewhere classified, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X211039592 for Amyloid-β disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries by Emily C Peters, Michael T Gee, Lukas N Pawlowski, Allison M Kath, Felipe D Polk, Christopher J Vance, Juliana L Sacoman and Paulo W Pires in Journal of Cerebral Blood Flow & Metabolism

Published
2021
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31. Contributors

Author

Abou-Zamzam Jr., Ahmed M., Abularrage, Christopher J., AbuRahma, Ali F., AbuRahma, Zachary, Acher, Charles W., Acosta, Stefan, Adelman, Mark A., Akar, Ahmet Rüçhan, Aldailami, Hasan, Alimi Sr., Yves S., Arbabi, Cassra N., Arko III, Frank R., Armstrong, David G., Arnaoutakis, K. Dean J., Arora, Subodh, Arthurs, Zachary M., Ascher, Enrico, Avgerinos, Efthymios D., Azarbal, Amir F., Aziz, Faisal, Azizzadeh, Ali, Baba, Takeshi, Back, Martin, Baig, M. Shadman, Bailey, Charles J., Bailey, Christopher R., Ballast, Jocelyn K., Barnes, Geoffrey D., Bates, Mark C., Baumeister, Ruediger G.H., Beaulieu, Robert J., Bechara, Carlos F., Beck, Adam W., Belkin, Michael, Ben-Haim, Simona, Benjamin, Elizabeth R., Benjamin, Marshall E., Bernas, Michael J., Bismuth, Jean, Biteman, Benjamin R., Bivalacqua, Trinity J., Bjarnason, Haraldur, Björck, Martin, Black III, James H., Blankensteijn, Jan D., Blas, Joseph-Vincent V., Bose, Saideep, Bower, Thomas C., Bowling, Frank L., Brahmandam, Anand, Brewster, Luke, Brinster, Clayton J., Broce, Mike, Brody, Fredrick, Brooke, Benjamin S., Brown, Kellie R., Bush, Ruth L., Calligaro, Keith D., Campbell, John E., Carpenter, Jeffrey P., Carsten III, Christopher G., Cayne, Neal S., Chaer, Rabih A., Chang, Kevin Z., Chaturvedi, Shruti, Chauhan, Yusuf, Cheng, Charlie, Chinnadurai, Ponraj, Chou, Elizabeth, Clair, Daniel G., Clark, Ross M., Clouse, W. Darrin, Coleman, Dawn M., Colling, Meaghan E., Comerota, Anthony J., Conrad, Mark F., Conte, Michael S., Corriere, Matthew A., Dakour-Aridi, Hanaa, Dalman, Ronald L., Dalsing, Michael C., Dardik, Alan, Darling, R. Clement, III, Davies, Mark G., Davila, Victor J., Dawson, David L., Deery, Sarah E., Demetriades, Demetrios, P.M. de Vries, Jean-Paul, Diab, Kaled, Dillavou, Ellen D., DiMuzio, Paul, Dosluoglu, Hasan H., Dossabhoy, Shernaz S., Dougherty, Matthew J., Dryjski, Maciej L., Duncan, Audra A., Eagleton, Matthew J., Earnshaw, Jonothan J., Eberhardt, Robert T., Edwards, Jeffrey B., Edwards, Matthew S., Ehlert, Bryan A., Eidt, John F., Eldrup-Jorgensen, Jens, Eliason, Jonathan L., Elsayed, Nadin, Eskandari, Mark K., Eslami, Mohammad H., Farber, Alik, Farooqui, Emaad, Figueroa, C. Alberto, Fishman, Steven J., Flohr, Tanya R., Forbes, Thomas L., Fox, Charles, Freischlag, Julie A., Gandhi, Sagar S., Geary, Randolph L., Ghaffarian, Amir, Giuliano, Katherine, Glaudemans, Andor W.J.M., Gloviczki, Peter, Go, Michael R., Gober, Leah M., Goldman, Matthew P., Goodney, Philip P., Gowda, Mamatha, Grunebach, Holly, Guzman, Raul J., Hallett, John W., Hamdan, Allen D., Hansen, Kimberley J., Harris, Linda M., Hartung, Olivier, Haut, Elliott R., Hemingway, Jake F., Henke, Peter K., Hicks, Caitlin W., Hinchliffe, Robert J., Hingorani, Anil P., Ho, Karen J., Hohmann, Stephen E., Holscher, Courtenay M., Howell, Caronae, Hu, Yiyuan David, Humphries, Misty D., Hunter, Glenn C., Hurie, Justin, Iafrati, Mark D., Illig, Karl A., Inaba, Kenji, İnan, Mustafa Bahadır, Israel, Ora, Jacobowitz, Glenn R., Jaffer, Iqbal H., Jain, Krishna M., Jayaraj, Arjun, Johanning, Jason M., Johnson, Brad, Jordan Jr., William D., Kabbani, Loay S., Kabnick, Lowell S., Kalish, Jeffrey, Kalra, Manju, Kanthi, Yogendra, Kashyap, Vikram S., Kauffman, Paulo, Kauvar, David S., Kayssi, Ahmed, Kernodle, Amber B., Khan, Sikandar Z., Kiguchi, Misaki, Killeen, Amanda L., Kim, Gloria Y., Kim, Paul J., Kim, Tanner I., Kirkwood, Melissa L., Kleiss, Simone F., Knepper, Jordan, Kraiss, Larry W., Kwong, Jonathan M., Lajoie, Lidie, Lal, Brajesh K., Lala, Salim, LaMuraglia, Glenn M., Landry, Gregory J., Langford, John T., Laredo, James, Lawrence, Peter F., Lawson, Jeffrey H., Lavery, Lawrence A., Lee, Byung-Boong, Lee, Jason T., Lee, Young, Lely, Rutger J., Leong, Beatriz V., Levy, Elad l., Lewis, Anthony J., Li, Jing, Lillehei, Craig W., Lilly, Michael P., Lindsay, Thomas F., Lipsett, Pamela A., Lipsitz, Evan C., Litchfield, Terry F., Litt, Harold, Liu, James L., Liu, Zhao-Jun, Lohr, Joann M., Lugo, Joanelle, Lum, Ying Wei, Lurie, Fedor, Lynch, Thomas G., Ma, Kirsten F., Macsata, Robyn, Magee, Gregory A., Makaroun, Michel S., Malas, Mahmoud B., Maldonado, Thomas S., Malekpour, Fatemeh, Maleti, Oscar, Malka, Kimberly T., Mansour, M. Ashraf, Mansukhani, Neel A., Markovic, Jovan N., Marks, Natalie A., McCabe, Dominick J.H., McCarthy, Cullen K., McKinsey, James F., McLafferty, Robert B., McMurray, Robert C., McQuinn, Christopher W., Menard, Matthew T., Mendes, Bernardo C., Mills Sr., Joseph L., Milner, Ross, Modrall, J. Gregory, Mohebali, Jahan, Mokin, Maxim, Moneta, Gregory L., Money, Samuel R., Montross, Brittany C., Moore, Wesley S., Morasch, Mark, Morcos, Ramez, Mousa, Albeir Y., Muck, Patrick E., Myers, Daniel J., Myers, Stuart I., Nagarsheth, Khanjan H., Naoum, Joseph J., Naylor, A. Ross, Neville, Richard F., Nguyen, Bao-Ngoc, Nguyen, Louis L., Niklason, Laura E., Obi, Andrea, Ohki, Takao, Orion, Kristine C., Orlino, Jon P., Passman, Marc A., Patel, Rhusheet, Pearce, Benjamin J., Perler, Bruce A., Perry, Robert J.T., Pires, Paulo W., Plotkin, Anastasia, Powell, Richard J., Pruitt, Eric Yates, Puggioni, Alessandra, Quiñones-Baldrich, William J., Quiroga, Elina, Quiroz, Hallie, Raffetto, Joseph D., Raju, Seshadri, Recht, Matthew H., Reed, Amy B., Reilly, Brendon P., Reitz, Katherine M., Repella, Tana L., Rialon, Kristy L., Ricco, Jean-Baptiste, Rigberg, David A., Rios, Anthony L., Ritenour, Amber E., Robins, J. Eli, Rockman, Caron B., Rockson, Stanley G., Roddy, Sean P., Rogers, Lee C., Rohrer, Michael J., Rosenfeld, Ethan S., Ross, John R., Rossi, Peter J., Rowe, Vincent L., Roy, Rishi A., Russell, Todd E., Rzucidlo, Eva M., Sadek, Mikel, Salata, Konrad, Sam II, Albert D., Sarac, Timur P., Sarıcaoğlu, Mehmet Cahit, Satiani, Bhagwan, Schanzer, Andres, Schermerhorn, Marc L., Schlieder, Ian, Schneider, Joseph, Schneider, Peter A., Schwartz, Samuel, Scully, Rebecca E., Sen, Indrani, Shah, Samir K., Shames, Murray L., Shanmugam, Victoria K., Sharafuddin, Mel J., Sharma, Gaurav, Shepard, Alexander D., Shestopalov, Alexander, Shin, Laura, Shortell, Cynthia K., Sidawy, Anton N., Simons, Jessica P., Singh, Michael J., Singh, Niten, Siracuse, Jeffrey J., Slart, Riemer H.J.A., Smeds, Matthew R., Smith, Danielle C., Snow, Rachael, Soden, Peter A., Sorber, Rebecca A., Srivastava, Sunita D., Stanley, James C., Starnes, Benjamin W., Starr, Jean E., Stern, Jordan R., Sternbergh III, W. Charles, Stone, Patrick A., Stoner, Michael C., Sutzko, Danielle C., Tarpara, Anand, Taylor, Spence M., Thaveau, Fabien, Thompson, Jonathan R., Timaran, Carlos H., Tingen, Joseph S., Treffalls, John A., Troutman, Douglas A., Tsai, Lillian L., Tzeng, Edith, Ulloa, Jesus G., Upchurch Jr., Gilbert R., Valentine, R. James, Velazquez, Omaida C., Vo, Victoria, Vowels, Travis, Wakefield, Thomas W., Waqas, Muhammad, Wasan, Suman M., Wasse, Haimanot (Monnie), Weaver, Fred A., Weiss, Clifford R., Weitz, Jeffrey I., Westin, Gregory G., Williams, Carlin A., Williams, Timothy K., Williamson, Ashley J., Witte, Marlys H., Woelfel, Stephanie L., Wolosker, Nelson, Woo, Karen, Wynn, Martha, Yammine, Halim, Yan, Qi, Yeh, Chin-Chin C., Yoo, Taehwan, Yuo, Theodore H., Zarkowsky, Devin S., Zettervall, Sara L., and Zhou, Wei

Published
2023
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32. elife-35316-v2.pdf

Author

Pires, Paulo W. and Earley, Scott

Subjects
Physiology, FOS: Biological sciences, 111601 Cell Physiology, Biophysics, food and beverages, FOS: Basic medicine, 60603 Animal Physiology - Systems, psychological phenomena and processes
Abstract

Hypoxia and ischemia are linked to oxidative stress, which can activate the oxidant-sensitive transient receptor potential ankyrin 1 (TRPA1) channel in cerebral artery endothelial cells, leading to vasodilation. We hypothesized that TRPA1 channels in endothelial cells are activated by hypoxia-derived reactive oxygen species, leading to cerebral artery dilation and reduced ischemic damage. Using isolated cerebral arteries expressing a Ca2+ biosensor in endothelial cells, we show that 4-hydroxynonenal and hypoxia increased TRPA1 activity, detected as TRPA1 sparklets. TRPA1 activity during hypoxia was blocked by antioxidants and by TRPA1 antagonism. Hypoxia caused dilation of cerebral arteries, which was disrupted by antioxidants, TRPA1 blockade and by endothelial cell-specific Trpa1 deletion (Trpa1 ecKO mice). Loss of TRPA1 channels in endothelial cells increased cerebral infarcts, whereas TRPA1 activation with cinnamaldehyde reduced infarct in wildtype, but not Trpa1 ecKO, mice. These data suggest that endothelial TRPA1 channels are sensors of hypoxia leading to vasodilation, thereby reducing ischemic damage.

Published
2019
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33. The angiotensin II receptor type 1b is the primary sensor of intraluminal pressure in cerebral artery smooth muscle cells

Author

Pires, Paulo W, Ko, Eun-A, Pritchard, Harry A T, Rudokas, Michael, Yamasaki, Evan, and Earley, Scott

Subjects
Mice, Inbred C57BL, Mice, Knockout, Receptor, Angiotensin, Type 1/genetics, TRPM Cation Channels/physiology, Losartan/pharmacology, Angiotensin II Type 1 Receptor Blockers/pharmacology, cardiovascular system, Pressure, Animals, Cerebral Arteries/cytology, hormones, hormone substitutes, and hormone antagonists, circulatory and respiratory physiology, Myocytes, Smooth Muscle/physiology
Abstract

KEY POINTS: The angiotensin II receptor type 1b (AT1 Rb ) is the primary sensor of intraluminal pressure in cerebral arteries. Pressure or membrane-stretch induced stimulation of AT1 Rb activates the TRPM4 channel and results in inward transient cation currents that depolarize smooth muscle cells, leading to vasoconstriction. Activation of either AT1 Ra or AT1 Rb with angiotensin II stimulates TRPM4 currents in cerebral artery myocytes and vasoconstriction of cerebral arteries. The expression of AT1 Rb mRNA is ∼30-fold higher than AT1 Ra in whole cerebral arteries and ∼45-fold higher in isolated cerebral artery smooth muscle cells. Higher levels of expression are likely to account for the obligatory role of AT1 Rb for pressure-induced vasoconstriction. ABSTRACT: Myogenic vasoconstriction, which reflects the intrinsic ability of smooth muscle cells to contract in response to increases in intraluminal pressure, is critically important for the autoregulation of blood flow. In smooth muscle cells from cerebral arteries, increasing intraluminal pressure engages a signalling cascade that stimulates cation influx through transient receptor potential (TRP) melastatin 4 (TRPM4) channels to cause membrane depolarization and vasoconstriction. Substantial evidence indicates that the angiotensin II receptor type 1 (AT1 R) is inherently mechanosensitive and initiates this signalling pathway. Rodents express two types of AT1 R - AT1 Ra and AT1 Rb - and conflicting studies provide support for either isoform as the primary sensor of intraluminal pressure in peripheral arteries. We hypothesized that mechanical activation of AT1 Ra increases TRPM4 currents to induce myogenic constriction of cerebral arteries. However, we found that development of myogenic tone was greater in arteries from AT1 Ra knockout animals compared with controls. In patch-clamp experiments using native cerebral arterial myocytes, membrane stretch-induced cation currents were blocked by the TRPM4 inhibitor 9-phenanthrol in both groups. Further, the AT1 R blocker losartan (1 μm) diminished myogenic tone and blocked stretch-induced cation currents in cerebral arteries from both groups. Activation of AT1 R with angiotensin II (30 nm) also increased TRPM4 currents in smooth muscle cells and constricted cerebral arteries from both groups. Expression of AT1 Rb mRNA was ∼30-fold greater than AT1 Ra in cerebral arteries, and knockdown of AT1 Rb selectively diminished myogenic constriction. We conclude that AT1 Rb , acting upstream of TRPM4 channels, is the primary sensor of intraluminal pressure in cerebral artery smooth muscle cells.

Published
2017
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47. Localized TRPA1 channel Ca 2+ signals stimulated by reactive oxygen species promote cerebral artery dilation

Author

Sullivan, Michelle N., primary, Gonzales, Albert L., additional, Pires, Paulo W., additional, Bruhl, Allison, additional, Leo, M. Dennis, additional, Li, Wencheng, additional, Oulidi, Agathe, additional, Boop, Frederick A., additional, Feng, Yumei, additional, Jaggar, Jonathan H., additional, Welsh, Donald G., additional, and Earley, Scott, additional

Published
2015
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