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

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

Patel P. D., Chen Y. L., Kasetti R. B., Maddineni P., Mayhew W., Millar J. C., Ellis D. Z., Sonkusare S. K., Zode G. S., Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma, 2021; Proc Natl Acad Sci U S A. 118(16) . PMID: | PMCID: PMC8072326

Daneva Z., Marziano C., Ottolini M., Chen Y. L., Baker T. M., Kuppusamy M., Zhang A., Ta H. Q., Reagan C. E., Mihalek A. D., Kasetti R. B., Shen Y., Isakson B. E., Minshall R. D., Zode G. S., Goncharova E. A., Laubach V. E., Sonkusare S. K., Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension, 2021; Proc Natl Acad Sci U S A. 118(17) . PMID: | PMCID: PMC8092599

Daneva Z., Ottolini M., Chen Y. L., Klimentova E., Kuppusamy M., Shah S. A., Minshall R. D., Seye C. I., Laubach V. E., Isakson B. E., Sonkusare S. K., Endothelial pannexin 1-TRPV4 channel signaling lowers pulmonary arterial pressure in mice, 2021; Elife. 10() . PMID: | PMCID: PMC8448527

Ottolini M., Hong K., Cope E. L., Daneva Z., DeLalio L. J., Sokolowski J. D., Marziano C., Nguyen N. Y., Altschmied J., Haendeler J., Johnstone S. R., Kalani M. Y., Park M. S., Patel R. P., Liedtke W., Isakson B. E., Sonkusare S. K., Local Peroxynitrite Impairs Endothelial Transient Receptor Potential Vanilloid 4 Channels and Elevates Blood Pressure in Obesity, 2020; Circulation. 141(16) 1318-1333. PMID: | PMCID: PMC7195859

Sonkusare SK, Bonev AD, Ledoux J, Liedtke W, Kotlikoff MI, Heppner TJ, Hill-Eubanks DC, Nelson MT, Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function., 2012; Science (New York, N.Y.). 336(6081) 597-601. PMID: 22556255 | PMCID: PMC3715993