Swapnil Sonkusare

Education

  • PhD, University of Arkansas for Medical Sciences
  • Postdoc, University of Vermont

Primary Appointment

  • Assistant Professor, Molecular Physiology and Biological Physics

Contact

Research Interest(s)

Microcirculation, vascular ion channels, calcium signaling mechanisms, endothelial cells, hypertension

Research Description

Endothelial cells line the inner walls of all the arteries, where they release substances that can cause vasodilation and lower the blood pressure. The loss of endothelium-dependent vasodilation increases vascular resistance and blood pressure in cardiovascular disorders. Thus, strategies to target the loss of endothelium-dependent vasodilation may have therapeutic benefit in cardiovascular disorders.

Under normal conditions, endothelium-dependent vasodilation is driven by increases in intracellular calcium. My laboratory studies the activity of individual calcium entry events in endothelial cells and their signaling targets under normal and disease conditions. We focus on two life-threatening disorders that are commonly associated with the loss of endothelial function- obesity and pulmonary hypertension. New findings reveal that calcium influx through TRPV4 ion channels, a key calcium entry pathway in endothelial cells, is drastically reduced in rodent models of obesity or pulmonary hypertension and in human patients. The overarching goal is to rescue TRPV4 ion channel activity in obesity and pulmonary hypertension by specifically targeting the causative mechanisms that lower TRPV4 ion channel activity. Our current studies attempt to improve the interaction between TRPV4 ion channels and their regulatory proteins (AKAP150 in systemic circulation and caveolin-1 in pulmonary circulation) in order to enhance endothelium-dependent vasodilation and decrease vascular resistance.

We use a combination of state-of-the-art techniques to achieve a comprehensive understanding of calcium signaling mechanisms that control vascular resistance, including high-speed confocal imaging of calcium signals, patch clamp electrophysiology to measure ion channel currents, and measurements of arterial diameter and blood pressure coupled with several transgenic mouse models.

Selected Publications

  • Ottolini M, Hong K, Sonkusare S. Calcium signals that determine vascular resistance. Wiley interdisciplinary reviews. Systems biology and medicine. 2019; e1448. PMID: 30884210
  • Artamonov M, Sonkusare S, Good M, Momotani K, Eto M, Isakson B, Le T, Cope E, Derewenda Z, Derewenda U, Somlyo A. RSK2 contributes to myogenic vasoconstriction of resistance arteries by activating smooth muscle myosin and the Na+/H+ exchanger. Science signaling. 2018;11(554). PMID: 30377223 | PMCID: PMC6474246
  • Hong K, Cope E, DeLalio L, Marziano C, Isakson B, Sonkusare S. TRPV4 (Transient Receptor Potential Vanilloid 4) Channel-Dependent Negative Feedback Mechanism Regulates Gq Protein-Coupled Receptor-Induced Vasoconstriction. Arteriosclerosis, thrombosis, and vascular biology. 2018. PMID: 29301784 | PMCID: PMC5823749
  • Xiao L, Hong K, Roberson C, Ding M, Fernandez A, Shen F, Jin L, Sonkusare S, Li X. Hydroxylated Fullerene: A Stellar Nanomedicine to Treat Lumbar Radiculopathy via Antagonizing TNF-α-Induced Ion Channel Activation, Calcium Signaling, and Neuropeptide Production. ACS biomaterials science & engineering. 2018;4(1): 266-277. PMID: 30038959 | PMCID: PMC6054467
  • Biwer L, Good M, Hong K, Patel R, Agrawal N, Looft-Wilson R, Sonkusare S, Isakson B. Non-Endoplasmic Reticulum-Based Calr (Calreticulin) Can Coordinate Heterocellular Calcium Signaling and Vascular Function. Arteriosclerosis, thrombosis, and vascular biology. 2017;38(1): 120-130. PMID: 29122814 | PMCID: PMC5746467
  • Marziano C, Hong K, Cope E, Kotlikoff M, Isakson B, Sonkusare S. 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. 2017;6(12). PMID: 29275372
  • Dalsgaard T, Sonkusare S, Teuscher C, Poynter M, Nelson M. Pharmacological inhibitors of TRPV4 channels reduce cytokine production, restore endothelial function and increase survival in septic mice. Scientific reports. 2016;6 33841. PMID: 27653046 | PMCID: PMC5031985
  • Mah W, Sonkusare S, Wang T, Azeddine B, Pupavac M, Carrot-Zhang J, Hong K, Majewski J, Harvey E, Russell L, Chalk C, Rosenblatt D, Nelson M, Séguin C. Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head. Journal of medical genetics. 2016. PMID: 27330106
  • Sonkusare S, Dalsgaard T, Bonev A, Nelson M. Inward rectifier potassium (Kir2.1) channels as end-stage boosters of endothelium-dependent vasodilators. The Journal of physiology. 2016. PMID: 26840527
  • Hill-Eubanks D, Gonzales A, Sonkusare S, Nelson M. Vascular TRP channels: performing under pressure and going with the flow. Physiology (Bethesda, Md.). 2014;29(5): 343-60. PMID: 25180264 | PMCID: PMC4214829
  • Krishnamoorthy G, Sonkusare S, Heppner T, Nelson M. 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. 2014;306(7): H981-8. PMID: 24508642 | PMCID: PMC3962638
  • Sonkusare S, Dalsgaard T, Bonev A, Hill-Eubanks D, Kotlikoff M, Scott J, Santana L, Nelson M. AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. Science signaling. 2014;7(333): ra66. PMID: 25005230 | PMCID: PMC4403000
  • Villalba N, Sonkusare S, Longden T, Tran T, Sackheim A, Nelson M, Wellman G, Freeman K. 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. 2014;3(6): e001474. PMID: 25527626 | PMCID: PMC4338739
  • Kharade S, Sonkusare S, Srivastava A, Thakali K, Fletcher T, Rhee S, Rusch N. The β3 subunit contributes to vascular calcium channel upregulation and hypertension in angiotensin II-infused C57BL/6 mice. Hypertension. 2012;61(1): 137-42. PMID: 23129698 | PMCID: PMC3748590
  • Sonkusare S, Bonev A, Ledoux J, Liedtke W, Kotlikoff M, Heppner T, Hill-Eubanks D, Nelson M. Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science (New York, N.Y.). 2012;336(6081): 597-601. PMID: 22556255 | PMCID: PMC3715993
  • Nystoriak M, O'Connor K, Sonkusare S, Brayden J, Nelson M, Wellman G. 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. 2010;300(3): H803-12. PMID: 21148767 | PMCID: PMC3064296
  • Thakali K, Kharade S, Sonkusare S, Rhee S, Stimers J, Rusch N. Intracellular Ca2+ silences L-type Ca2+ channels in mesenteric veins: mechanism of venous smooth muscle resistance to calcium channel blockers. Circulation research. 2010;106(4): 739-47. PMID: 20044515 | PMCID: PMC2855128
  • Télémaque S, Sonkusare S, Grain T, Rhee S, Stimers J, Rusch N, Marsh J. Design of mutant beta2 subunits as decoy molecules to reduce the expression of functional Ca2+ channels in cardiac cells. The Journal of pharmacology and experimental therapeutics. 2008;325(1): 37-46. PMID: 18184831
  • Sonkusare S, Fraer M, Marsh J, Rusch N. Disrupting calcium channel expression to lower blood pressure: new targeting of a well-known channel. Molecular interventions. 2007;6(6): 304-10. PMID: 17200457
  • Pathan A, Viswanad B, Sonkusare S, Ramarao P. Chronic administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats. Life sciences. 2006;79(23): 2209-16. PMID: 16904700
  • Sonkusare S, Palade P, Marsh J, Telemaque S, Pesic A, Rusch N. Vascular calcium channels and high blood pressure: pathophysiology and therapeutic implications. Vascular pharmacology. 2006;44(3): 131-42. PMID: 16427812
  • Sonkusare S, Srinivasan K, Kaul C, Ramarao P. Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats. Life sciences. 2005;77(1): 1-14. PMID: 15848214
  • Sonkusare S, Kaul C, Ramarao P. Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope. Pharmacological research : the official journal of the Italian Pharmacological Society. 2004;51(1): 1-17. PMID: 15519530