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Department of Anesthesiology/Critical Care Medicine
The Johns Hopkins University School of Medicine
720 Rutland Ave, Ross 372
Baltimore, MD 21205
The primary goal of Dr. Nicholas Flavahan’s research is to elucidate the cellular interactions and subcellular signaling pathways that control normal vascular function and regulate the initiation of vascular disease. Normal blood vessel function is essential for survival. Blood vessels must be able to integrate diverse physical and chemical signals and respond immediately by regulating blood flow to different organs in response to their needs and the collective good of the organism. They must also be able to adapt to chronic changes in organ requirements by remodeling to alter blood vessel caliber (e.g., arteriogenesis) or by altering the density of the vascular network (e.g., angiogenesis). Dysfunction of this system, for example in response to injury, environmental stimuli, or genetic susceptibility, results in vascular disease and inappropriate growth or remodeling of the vascular system (e.g., arteriosclerosis), or altered responsiveness of the vessel wall (e.g., vasospasm, hypertension).
Dr. Flavahan and his team use a multidisciplinary approach to investigate vascular function. Their methods range from biochemical or molecular analyses of cellular mediators and cell signaling mechanisms in cultured vascular cells to physiological assessment and fluorescent microscopic imaging of signaling systems in isolated blood vessels. A major component of their research involves the analysis of isolated arterioles. Arterioles are very small blood vessels with an internal diameter smaller than a human hair and comprising two to three cell layers in thickness: one to two layers of smooth muscle cells, which determine constriction or blood vessel diameter, and one layer of endothelial cells, which regulate blood cells and smooth muscle cells. Despite their small size, arterioles are responsible for controlling the peripheral resistance of the cardiovascular system and therefore help determine organ blood flow. Dr. Flavahan’s specialized systems enable his group to directly assess the function and signaling systems within these tiny structures (Figure 1). Dr. Flavahan and his team are pursuing several major projects that focus on understanding 1) the mechanisms underlying mechanotransduction in cultured and native smooth muscle and its role in vascular disease (including hypertension), 2) the role of reactive oxygen species (ROS) in the physiological control of the vascular system, 3) mechanisms contributing to occlusive vascular diseases (e.g., scleroderma, arteriosclerosis), 4) mechanisms underlying the abnormal vasoreactivity of Raynaud’s phenomenon (cold-induced vasospasm) and scleroderma, 5) mechanisms regulating the life cycle of vascular cells, including development, differentiation, and apoptosis, and 6) the role of the sympathetic nervous system and x-adrenergic receptors in vascular function and disease.
Dr. Flavahan and his team are currently developing and characterizing new preclinical models of Raynaud’s phenomenon and peripheral vasospasm. Vasospasm is exaggerated constriction or closure of blood vessels that leads to excessive reductions in blood flow. Cold exposure causes a decrease in skin blood flow as part of a normal, protective response to reduce heat loss. The reduction in blood flow is accomplished by a reflex increase in sympathetic nerve activity and by a direct sensitizing effect of cold to amplify sympathetic vasoconstriction. In individuals with Raynaud’s phenomenon, the vascular response to the direct effect of cold is exaggerated such that cold exposure causes vasospasm. Raynaud's phenomenon is one of the earliest symptoms of a more systemic disease known as diffuse scleroderma. Raynaud’s phenomen occurs in approximately 95% of scleroderma patients, but only a small percentage (<1%) of individuals with Raynaud’s phenomenon will develop scleroderma. In scleroderma, vasospasm occurs not only in the skin but also in the kidney, heart, lung, and gastrointestinal tract. These blood vessels subsequently develop structural lesions that further compromise blood flow to these important organs. Dr. Flavahan’s group has identified the molecular mechanisms that are responsible for cold-induced constriction or vasospasm of skin blood vessels and that might contribute to the vasospastic episodes of Raynaud’s phenomenon and scleroderma. They also have identified the natural thermosensor or thermometer in skin blood vessels. In response to cold exposure, the thermosensor causes the relocation of x2C-adrenergic receptors (x2C-ARs) from intracellular stores (transGolgi network), where they are normally retained, to the surface of the smooth muscle cells, where they signal the blood vessel to constrict and decrease blood flow. The thermosensor that initiates this process is the cell’s mitochondria, where cellular energy production is regulated. In response to cold exposure, the mitochondria generate ROS, which activate a signaling pathway (Rho, Rho kinase) responsible for the relocation of the x2C-ARs. Dr. Flavahan is hopeful that drugs or techniques aimed at inhibiting the thermosensing mechanism (ROS, Rho, Rho kinase) or the x2C-AR can be developed to provide novel and effective therapy for the vasospastic episodes of Raynaud’s phenomenon and scleroderma. He is currently evaluating potential therapies in new preclinical models of the disease process and in human clinical trials.
- *Thompson-Torgerson CS, Holowatz LA, Flavahan NA, Kenney WL. Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin. Am J Physiol Heart Circ Physiol 292(4):H1700–5, 2007.
- *Accompanying Editorial: Johnson JM. Mechanisms of vasoconstriction with direct skin cooling in humans. Am J Physiol Heart Circ Physiol 292(4):H1690–1, 2007.
- Eid AH, Maiti K, Mitra S, Chotani MA, Flavahan S, Bailey SR, Thompson-Torgerson CS, Flavahan NA. Estrogen increases smooth muscle expression of alpha2C-adrenoceptors and cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol 293(3):H1955–61, 2007.
- Thompson-Torgerson CS, Holowatz LA, Flavahan NA, Kenney WL. Rho kinase-mediated cold-induced cutaneous vasoconstriction is augmented in aged human skin. Am J Physiol Heart Circ Physiol 293(1):H30–6, 2007.
- Bailey SR, Mitra S, Flavahan S, Bergdall VK, Flavahan NA. In vivo endothelial denudation disrupts smooth muscle caveolae and differentially impairs agonist-induced constriction in small arteries. J Cardiovasc Pharmacol 49(4):183-90, 2007.
- Flavahan, NA.Regulation of vascular reactivity in Scleroderma: new insights into Raynaud's phenomenon. Rheum Dis Clin N Am 34(1):81–7, 2008.
Laboratory Members/Key Associates
Sheila Flavahan, RN
Sheila Flavahan, RN, Lab Manager
Chung-Lin Chen, PhD
Pierre-Antoine Crassous, PhD
Aditya Goel, PhD
Mansoor Mozayan, MBBS, PhD
Jian-Hong Zhu, PhD