Associate Professor, Molecular Physiology and Biological Physics
- PhD, Pharmacology, University of Arkansas for Medical Sciences
- Postdoc, Vascular ion channels, University of Vermont
Biophysics, Cardiovascular Biology, Physiology
Identify the calcium signaling abnormalities that lead to vascular dysfunction and blood pressure elevation in cardiovascular disorders
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.