Swapnil Sonkusare

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Primary Appointment

Associate Professor, Molecular Physiology and Biological Physics

Education

  • PhD, Pharmacology, University of Arkansas for Medical Sciences
  • Postdoc, Vascular ion channels, University of Vermont

Research Disciplines

Biophysics, Biophysics & Structural Biology, Cardiovascular Biology, Physiology

Research Interests

Identify the calcium signaling abnormalities that lead to vascular dysfunction and blood pressure elevation in cardiovascular disorders

Research Description

The Sonkusare laboratory studies the role of ion channels and calcium signaling mechanisms in regulating vascular function and blood pressure. Constriction of small arteries is a crucial determinant of blood pressure. Smooth muscle cells are the contractile cells in the arterial wall, whereas endothelial cells regulate smooth muscle contraction. Calcium signaling mechanisms in endothelial and smooth muscle cells are critical controllers of arterial constriction. Moreover, abnormal calcium handling in endothelial and smooth muscle cells has been implicated in blood pressure elevation in hypertension. Thus, strategies targeting arterial calcium signaling abnormalities may have therapeutic benefits in hypertension.
We use numerous transgenic knockout mouse models and a combination of state-of-the-art techniques, including high-speed confocal imaging of individual calcium signals, patch-clamp electrophysiology to assess the activity of calcium channels (proteins that allow calcium flux), dSTORM super-resolution imaging to visualize calcium channel proteins, and measurements of arterial diameter and blood pressure. For our most current list of publications, please visit https://pubmed.ncbi.nlm.nih.gov/?term=Sonkusare+Swapnil%5BAuthor%5D&sort=date.
A major focus of current studies is the role of TRP ion channels in blood pressure regulation. TRP channels are a major calcium entry pathway in endothelial and smooth muscle cells. TRP channels have signaling linkages with other calcium channels, potassium channels, and nitric oxide synthases. Multiple physiological stimuli in endothelial and smooth muscle cells can activate TRP channels in arterial walls, including flow/shear stress, G-protein coupled receptor signaling, and intraluminal pressure. The ultimate goal is to discover specific abnormalities in calcium signaling mechanisms that can be targeted for therapeutic benefit in the following disease conditions:
1. Obesity-induced hypertension. Obesity has become a life-threatening health concern and a major risk factor for cardiovascular disease, including hypertension and stroke. Endothelial cell dysfunction is a hallmark of obesity. We investigate the mechanisms underlying impaired endothelial calcium signaling and potential ways to target this abnormality. Our ongoing studies suggest an essential role for vascular inflammation and resultant oxidative stress in impairing endothelial and smooth muscle calcium signaling in obesity.
2. Pulmonary hypertension. Pulmonary hypertension (PH) is a serious disorder characterized by elevated pulmonary arterial pressure (PAP). The contractile state of small pulmonary arteries determines PAP. Our previous studies showed a key role for Pannexin 1 (ATP efflux pathway), purinergic signaling, and TRP channels in controlling pulmonary artery diameter and PAP. Current studies determine whether impaired activity of these proteins contributes to pulmonary artery constriction and remodeling in pulmonary hypertension.
3. Hypertension. Nearly one out of two adults has hypertension in the US. Abnormal calcium handling in arterial smooth muscle cells has been implicated in hypertension. We study calcium signaling mechanisms in smooth muscle cells that regulate blood pressure under normal conditions and are impaired in hypertension. We use mouse models of hypertension and tissue from hypertensive patients to delineate cellular mechanisms underlying arterial dysfunction.
4. Atherosclerosis. Atherosclerosis is a chronic inflammatory disease of the arteries and is the underlying cause of about 50% of all deaths in western society. Our studies delineate vascular calcium signaling abnormalities that contribute to the pathogenesis of atherosclerosis.
5. Lung ischemia-reperfusion injury. Outcomes of lung transplantation are poor, with nearly half of the patients die within 6-7 years post-transplant. Lung ischemia-reperfusion injury (IRI) is a significant cause of death post-transplant. Our studies show an essential role for capillary endothelial TRP channels in lung IRI, and demonstrate beneficial effects of TRP channel inhibitors in preventing lung IRI.

Personal Statement

The research in my laboratory focuses on the regulation of blood flow and blood pressure by calcium signaling mechanisms in the vascular wall. I have investigated vascular calcium channels in health and disease throughout my scientific career. My ultimate goals are to define the abnormalities in vascular calcium signaling mechanisms in cardiovascular disorders and to identify novel therapeutic targets. My laboratory routinely uses high-end calcium imaging, superresolution imaging, patch-clamp electrophysiology, vascular assays, mouse models of vascular disorders, and transgenic mice. Current NIH- and AHA-funded studies in my laboratory use this unique combination of techniques to address 1) new calcium signaling mechanisms that control vascular contractility and blood pressure in systemic and pulmonary vasculature; 2) contribution of impaired vascular calcium signaling and vascular inflammation to obesity-induced hypertension.
I invite you to join our group and perform cutting-edge research on vascular calcium signaling mechanisms!

Training

  • Basic Cardiovascular Research Training Grant
  • Training in Molecular Biophysics
  • Training in the Pharmacological Sciences

Selected Publications

2024

Wolpe, A. G., Luse, M. A., Baryiames, C., Schug, W. J., Wolpe, J. B., Johnstone, S. R., . . . Isakson, B. E. (2024). Pannexin-3 stabilizes the transcription factor Bcl6 in a channel-independent manner to protect against vascular oxidative stress. SCIENCE SIGNALING, 17(821). doi:10.1126/scisignal.adg2622

2023

Kuppusamy, M., Ta, H. Q., Davenport, H. N., Bazaz, A., Kulshrestha, A., Daneva, Z., . . . Sonkusare, S. K. (2023). Purinergic P2Y2 receptor-induced activation of endothelial TRPV4 channels mediates lung ischemia-reperfusion injury. SCIENCE SIGNALING, 16(808). doi:10.1126/scisignal.adg1553

Villalba, N., Sackheim, A. M., Lawson, M. A., Haines, L., Chen, Y. -L., Sonkusare, S. K., . . . Freeman, K. (2023). The Polyanionic Drug Suramin Neutralizes Histones and Prevents Endotheliopathy. JOURNAL OF IMMUNOLOGY, 211(4), 648-657. doi:10.4049/jimmunol.2200703

Ruddiman, C. A., Peckham, R., Luse, M. A., Chen, Y. -L., Kuppusamy, M., Corliss, B. A., . . . Isakson, B. E. (2023). Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1. JCI INSIGHT, 8(9). doi:10.1172/jci.insight.165715

Wong, D., Auguste, G., Lino Cardenas, C. L., Turner, A. W., Chen, Y., Song, Y., . . . Miller, C. L. (2023). FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells. CIRCULATION RESEARCH, 132(9), 1144-1161. doi:10.1161/CIRCRESAHA.122.321692

Daneva, Z., Chen, Y. -L., Ta, H. Q., Manchikalapudi, V., Bazaz, A., Laubach, V. E., & Sonkusare, S. K. (2023). Endothelial IK and SK channel activation decreases pulmonary arterial pressure and vascular remodeling in pulmonary hypertension. PULMONARY CIRCULATION, 13(1). doi:10.1002/pul2.12186

2022

Keller, T. C. S., Lechauve, C., Keller, A. S., Broseghini-Filho, G. B., Butcher, J. T., Page, H. R. A., . . . Isakson, B. E. (2022). Endothelial alpha globin is a nitrite reductase. NATURE COMMUNICATIONS, 13(1). doi:10.1038/s41467-022-34154-3

Chen, Y. -L., Daneva, Z., Kuppusamy, M., Ottolini, M., Baker, T. M., Klimentova, E., . . . Sonkusare, S. K. (2022). Novel Smooth Muscle Ca2+-Signaling Nanodomains in Blood Pressure Regulation. CIRCULATION, 146(7), 548-564. doi:10.1161/CIRCULATIONAHA.121.058607

Chen, Y. -L., & Sonkusare, S. K. (2022). Mechanosensitive Angiotensin II Receptor Signaling in Pressure-Induced Vasoconstriction. JOURNAL OF THE AMERICAN HEART ASSOCIATION, 11(4). doi:10.1161/JAHA.121.024740

Sonkusare, S. K., & Laubach, V. E. (2022). Endothelial TRPV4 channels in lung edema and injury. ROLE OF TRPV4 CHANNELS IN DIFFERENT ORGAN SYSTEMS, 89, 43-62. doi:10.1016/bs.ctm.2022.07.001

2021

Kuppusamy, M., Ottolini, M., & Sonkusare, S. K. (2021). Role of TRP ion channels in cerebral circulation and neurovascular communication. NEUROSCIENCE LETTERS, 765. doi:10.1016/j.neulet.2021.136258

Daneva, Z., Ottolini, M., Chen, Y. L., Klimentova, E., Kuppusamy, M., Shah, S. A., . . . Sonkusare, S. K. (2021). Endothelial pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure in mice. ELIFE, 10. doi:10.7554/eLife.67777

Wenceslau, C. F., McCarthy, C. G., Earley, S., England, S. K., Filosa, J. A., Goulopoulou, S., . . . Webb, R. C. (2021). Guidelines for the measurement of vascular function and structure in isolated arteries and veins. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 321(1), H77-H111. doi:10.1152/ajpheart.01021.2020

Haywood, N., Ta, H. Q., Zhang, A., Charles, E. J., Rotar, E., Noona, S., . . . Laubach, V. E. (2022). Endothelial Transient Receptor Potential Vanilloid 4 Channels Mediate Lung Ischemia-Reperfusion Injury. ANNALS OF THORACIC SURGERY, 113(4), 1256-1264. doi:10.1016/j.athoracsur.2021.04.052

Daneva, Z., Marziano, C., Ottolini, M., Chen, Y. -L., Baker, T. M., Kuppusamy, M., . . . Sonkusare, S. K. (2021). Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 118(17). doi:10.1073/pnas.2023130118

Patel, P. D., Chen, Y. -L., Kasetti, R. B., Maddineni, P., Mayhew, W., Millar, J. C., . . . Zode, G. S. (2021). Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 118(16). doi:10.1073/pnas.2022461118

Ottolini, M., & Sonkusare, S. K. (2021). The Calcium Signaling Mechanisms in Arterial Smooth Muscle and Endothelial Cells.. Comprehensive Physiology, 11(2), 1831-1869. doi:10.1002/cphy.c200030

Jander, K., Greulich, J., Gonnissen, S., Ale-Agha, N., Goy, C., Jakobs, P., . . . Altschmied, J. (2021). Extra-Nuclear Functions of the Transcription Factor Grainyhead-Like 3 in the Endothelium-Interaction with Endothelial Nitric Oxide Synthase. ANTIOXIDANTS, 10(3). doi:10.3390/antiox10030428

Maier-Begandt, D., Comstra, H. S., Molina, S. A., Krueger, N., Ruddiman, C. A., Chen, Y. -L., . . . Isakson, B. E. (2021). A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNFα-induced increases in endothelial permeability. SCIENCE SIGNALING, 14(672). doi:10.1126/scisignal.aba2940

Haywood, N., Ta, H. Q., Rotar, E., Daneva, Z., Sonkusare, S. K., & Laubach, V. E. (2021). Role of the purinergic signaling network in lung ischemia-reperfusion injury. CURRENT OPINION IN ORGAN TRANSPLANTATION, 26(2), 250-257. doi:10.1097/MOT.0000000000000854

Chen, Y. L., Baker, T. M., Lee, F., Shui, B., Lee, J. C., Tvrdik, P., . . . Sonkusare, S. K. (2021). Calcium Signal Profiles in Vascular Endothelium from Cdh5-GCaMP8 and Cx40-GCaMP2 Mice. JOURNAL OF VASCULAR RESEARCH, 58(3), 159-171. doi:10.1159/000514210

2020

Ottolini, M., Daneva, Z., Chen, Y. -L., Cope, E. L., Kasetti, R. B., Zode, G. S., & Sonkusare, S. K. (2020). Mechanisms underlying selective coupling of endothelial Ca2+signals with eNOSvs. IK/SK channels in systemic and pulmonary arteries. JOURNAL OF PHYSIOLOGY-LONDON, 598(17), 3577-3596. doi:10.1113/JP279570

Biwer, L. A., Askew-Page, H. R., Hong, K., Milstein, J., Johnstone, S. R., Macal, E., . . . Isakson, B. E. (2020). Endothelial calreticulin deletion impairs endothelial function in aged mice. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 318(5), H1041-H1048. doi:10.1152/ajpheart.00586.2019

Ottolini, M., Hong, K., Cope, E. L., Daneva, Z., DeLalio, L. J., Sokolowski, J. D., . . . Sonkusare, S. K. (2020). Local Peroxynitrite Impairs Endothelial Transient Receptor Potential Vanilloid 4 Channels and Elevates Blood Pressure in Obesity. CIRCULATION, 141(16), 1318-1333. doi:10.1161/CIRCULATIONAHA.119.043385

Patel, P. D., Kasetti, R. B., Sonkusare, S. K., & Zode, G. S. (2020). Technical brief: Direct, real-time electrochemical measurement of nitric oxide in ex vivo cultured human corneoscleral segments. MOLECULAR VISION, 26, 434-444. Retrieved from https://www.webofscience.com/

Chen, Y. -L., & Sonkusare, S. K. (2020). Endothelial TRPV4 channels and vasodilator reactivity. ION CHANNELS AND CALCIUM SIGNALING IN THE MICROCIRCULATION, 85, 89-117. doi:10.1016/bs.ctm.2020.01.007

2019

Kruger, N., Biwer, L. A., Good, M. E., Ruddiman, C. A., Wolpe, A. G., DeLalio, L. J., . . . Isakson, B. E. (2020). Loss of Endothelial FTO Antagonizes Obesity-Induced Metabolic and Vascular Dysfunction. CIRCULATION RESEARCH, 126(2), 232-242. doi:10.1161/CIRCRESAHA.119.315531

Daneva, Z., Laubach, V. E., & Sonkusare, S. K. (2019). Novel regulators and targets of redox signaling in pulmonary vasculature. CURRENT OPINION IN PHYSIOLOGY, 9, 87-93. doi:10.1016/j.cophys.2019.04.026

Ottolini, M., Hong, K., & Sonkusare, S. K. (2019). Calcium signals that determine vascular resistance. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE, 11(5). doi:10.1002/wsbm.1448

2018

Artamonov, M. V., Sonkusare, S. K., Good, M. E., Momotani, K., Eto, M., Isakson, B. E., . . . Somlyo, A. V. (2018). RSK2 contributes to myogenic vasoconstriction of resistance arteries by activating smooth muscle myosin and the Na+/H+ exchanger. SCIENCE SIGNALING, 11(554). doi:10.1126/scisignal.aar3924

Hong, K., Cope, E. L., DeLalio, L. J., Marziano, C., Isakson, B. E., & Sonkusare, S. K. (2018). TRPV4 (Transient Receptor Potential Vanilloid 4) Channel-Dependent Negative Feedback Mechanism Regulates Gq Protein-Coupled Receptor-Induced Vasoconstriction. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 38(3), 542-554. doi:10.1161/ATVBAHA.117.310038

2017

Marziano, C., Hong, K., Cope, E. L., Kotlikoff, M. I., Isakson, B. E., & Sonkusare, S. K. (2017). Nitric Oxide-Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries. JOURNAL OF THE AMERICAN HEART ASSOCIATION, 6(12). doi:10.1161/JAHA.117.007157

Xiao, L., Hong, K., Roberson, C., Ding, M., Fernandez, A., Shen, F., . . . Li, X. (2018). Hydroxylated Fullerene: A Stellar Nanomedicine to Treat Lumbar Radiculopathy via Antagonizing TNF-α-lnduced Ion Channel Activation, Calcium Signaling, and Neuropeptide Production. ACS BIOMATERIALS SCIENCE & ENGINEERING, 4(1), 266-277. doi:10.1021/acsbiomaterials.7b00735

Biwer, L. A., Good, M. E., Hong, K., Patel, R. K., Agrawal, N., Looft-Wilson, R., . . . Isakson, B. E. (2018). Non-Endoplasmic Reticulum-Based Calr (Calreticulin) Can Coordinate Heterocellular Calcium Signaling and Vascular Function. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 38(1), 120-130. doi:10.1161/ATVBAHA.117.309886

2016

Dalsgaard, T., Sonkusare, S. K., Teuscher, C., Poynter, M. E., & Nelson, M. T. (2016). Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice. SCIENTIFIC REPORTS, 6. doi:10.1038/srep33841

Mah, W., Sonkusare, S. K., Wang, T., Azeddine, B., Pupavac, M., Carrot-Zhang, J., . . . Seguin, C. (2016). Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head. JOURNAL OF MEDICAL GENETICS, 53(10), 705-709. doi:10.1136/jmedgenet-2016-103829

Sonkusare, S. K., Dalsgaard, T., Bonev, A. D., & Nelson, M. T. (2016). Inward rectifier potassium (Kir2.1) channels as end-stage boosters of endothelium-dependent vasodilators. JOURNAL OF PHYSIOLOGY-LONDON, 594(12), 3271-3285. doi:10.1113/JP271652

2014

Villalba, N., Sonkusare, S. K., Longden, T. A., Tran, T. L., Sackheim, A. M., Nelson, M. T., . . . Freeman, K. (2014). Traumatic Brain Injury Disrupts Cerebrovascular Tone Through Endothelial Inducible Nitric Oxide Synthase Expression and Nitric Oxide Gain of Function. JOURNAL OF THE AMERICAN HEART ASSOCIATION, 3(6). doi:10.1161/JAHA.114.001474

Hill-Eubanks, D. C., Gonzales, A. L., Sonkusare, S. K., & Nelson, M. T. (2014). Vascular TRP Channels: Performing Under Pressure and Going with the Flow. PHYSIOLOGY, 29(5), 343-360. doi:10.1152/physiol.00009.2014

Sonkusare, S. K., Dalsgaard, T., Bonev, A. D., Hill-Eubanks, D. C., Kotlikoff, M. I., Scott, J. D., . . . Nelson, M. T. (2014). AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. SCIENCE SIGNALING, 7(333). doi:10.1126/scisignal.2005052

Krishnamoorthy, G., Sonkusare, S. K., Heppner, T. J., & Nelson, M. T. (2014). Opposing roles of smooth muscle BK channels and ryanodine receptors in the regulation of nerve-evoked constriction of mesenteric resistance arteries. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 306(7), H981-H988. doi:10.1152/ajpheart.00866.2013

2012

Kharade, S. V., Sonkusare, S. K., Srivastava, A. K., Thakali, K. M., Fletcher, T. W., Rhee, S. W., & Rusch, N. J. (2013). The β3 Subunit Contributes to Vascular Calcium Channel Upregulation and Hypertension in Angiotensin II-Infused C57BL/6 Mice. HYPERTENSION, 61(1), 137-+. doi:10.1161/HYPERTENSIONAHA.112.197863

Sonkusare, S. K., Bonev, A. D., Ledoux, J., Liedtke, W., Kotlikoff, M. I., Heppner, T. J., . . . Nelson, M. T. (2012). Elementary Ca2+ Signals Through Endothelial TRPV4 Channels Regulate Vascular Function. SCIENCE, 336(6081), 597-601. doi:10.1126/science.1216283

2010

Nystoriak, M. A., O'Connor, K. P., Sonkusare, S. K., Brayden, J. E., Nelson, M. T., & Wellman, G. C. (2011). Fundamental increase in pressure-dependent constriction of brain parenchymal arterioles from subarachnoid hemorrhage model rats due to membrane depolarization. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 300(3), H803-H812. doi:10.1152/ajpheart.00760.2010