My research program is focused on defining the microvascular control mechanisms that underlie tissue blood flow regulation, and on gaining a better understanding of how these mechanisms can change with (1) the rapid vascular growth that accompanies juvenile maturation, (2) the development of salt-sensitive hypertension, and (3) high dietary salt intake in the absence of hypertension. Much of the work toward these goals is centered on the endothelium and its ability to influence vascular tone through the release of different vasoactive molecules. Many of our studies are conducted on exteriorized tissue preparations, and rely on the use of intravital microscopy (in combination with various optical and micropipette-based techniques) to directly evaluate microvascular function in vivo. These approaches are complemented by the use of various cellular and molecular approaches, and by quantitative image analysis. Specific projects we are currently working on include:
We have demonstrated that high dietary salt intake, in the absence of hypertension, can lead to a loss of microvascular nitric oxide (NO) activity, and are now investigating the mechanism by which dietary salt suppresses microvascular NO levels. In normotensive rats fed a high-salt diet, we have found that endothelium-derived NO is prematurely oxidized by reactive oxygen species (ROS) in the microvascular wall. Western analysis indicates that high salt intake does not change microvascular expression of the antioxidant enzymes Cu/Zn superoxide dismutase (Cu/Zn SOD), catalase, or glutathione peroxidase, or expression of the superoxide-generating enzymes NAD(P)H oxidase or xanthine oxidase. However, pre- and postcapillary Cu/Zn SOD activity appears to be chronically suppressed in vivo, and this is coupled with elevated activities of NAD(P)H oxidase and xanthine oxidase. We are currently working to establish the mechanism by which the activity of these oxidant enzymes is increased in salt-fed rats. We have also found that in the microcirculation of salt-fed mice, “uncoupled” nitric oxide synthase (due to low levels of the cofactor BH4) appears to be the predominant source of arteriolar ROS under both resting conditions and during endothelium-dependent dilation. We are now working to more firmly establish these mechanistic links between dietary salt and microvascular control.
We have previously reported that normal juvenile growth is accompanied by dramatic changes in microvascular structure and function. For example, in rat skeletal muscle, the rapid growth that occurs between 4 and 8 weeks of age is accompanied by the development of shear stress sensitivity in the microvascular endothelium. The resulting onset of shear-dependent NO release plays an important role in microvascular regulation. Hydrogen peroxide also emerges as an important endothelial vasoactive factor during growth. We are currently working to understand how different endothelial cell signaling pathways that mediate vasoactive factor release become operational during juvenile growth, leading to a dramatic shift in the specific factors that mediate endothelium dependent dilation during this period.
Selected Publications:
Boegehold MA. Vascular remodeling and rarefaction in hypertension. In: Comprehensive Hypertension, ed: G.Lip and John Hall. New York: Mosby Elsevier, 2007.
Marvar PJ, Falck JR, Boegehold MA. High dietary salt reduces the contribution of 20-HETE to arteriolar oxygenresponsiveness in skeletal muscle. Am J Physiol Heart Circ Physiol 292: H1507-H1515, 2007.
Nurkiewicz TR, Boegehold MA. High salt intake reduces endothelium-dependent dilation of mouse arterioles via superoxide anion generated from nitric oxide synthase. Am J Physiol Reg Int Physiol 292: R1550-R1556, 2007.
Marvar PJ, Hammer LW, Boegehold MA. Hydrogen peroxide-dependent arteriolar dilation in contracting muscle of rats fed normal and high salt diets. Microcirculation 14: 779-791, 2007.
Balch Samora J, Frisbee JC, Boegehold MA. Hydrogen peroxide emerges as a regulator of arteriolar tone during juvenile growth of the arteriolar network. Microcirculation 15: 151-161, 2008.
Balch Samora J, Frisbee JC, Boegehold MA. Increased myogenic responsiveness of skeletal muscle arterioles with juvenile growth. Am J Physiol Heart Circ Physiol 294: H2344-H2351, 2008.
Nayeem MA, Ponnoth DS, Boegehold MA, Zeldin DC, Falck JR, Mustafa SJ. High salt diet enhances mouse aortic relaxation through adenosine A2A receptor via CYP epoxygenases. Am J Physiol Reg Int Comp Physiol 296:R567-R574, 2009.
Nurkiewicz TR, Porter DW, Hubbs AF, Stone S, Chen BT, Frazer DG, Boegehold MA, Castranova V. Pulmonary nanoparticle exposure disrupts systemic microvascular nitric oxide signaling. Toxicol Sci 110:191-203, 2009.
Frisbee JC, Hollander JM, Brock RW, Yu HG, Boegehold MA. Integration of pathways for skeletal muscle arteriolar reactivity in the metabolic syndrome. Am J Physiol Reg Int Comp Physiol 296:R1771-R1782, 2009.
Balch Samora J, Goodwill AG, Frisbee JC, Boegehold MA. Growth-dependent changes in the contribution of carbon monoxide to arteriolar function. J Vasc Res 47:23-34, 2010.
Nurkiewicz TR, Wu G, Li P, Boegehold MA. Decreased arteriolar tetrahydrobiopterin is linked to superoxide generation from nitric oxide synthase in mice fed high salt. Microcirculation 17: 147–157, 2010.
Nayeem MA, Zeldin D, Boegehold MA, Morisseau C, Marowsky A, Ponnoth D, Roush K, Falck J. Modulation by salt intake of the vascular response mediated through adenosine A2A receptor: role of CYP epoxygenase and soluble epoxide hydrolase. Am J Physiol Reg Int Comp Physiol 299: R325-R333, 2010.
Lab Personnel:
Kim Wix - Research Assistant II
Lori Kang, Ph.D.- Postdoctoral Fellow
Lori Kang, Ph.D., Dr. Matthew Boegehold and Kim Wix
