My laboratory uses an integrative approach, including the use of molecular, genetic and pharmacological methods, to address important questions related to cardiovascular disease. With the advances in genetic technology that has allowed for manipulation of the mouse genome and with the mouse being ideally suited as a model of human disease, all of our studies make use of these extremely powerful tools to study vascular function. Examination of vascular function, particularly endothelial function, is important considering that endothelial function has a major impact on the vessel wall and has emerged as an independent predictor of cardiovascular disease and events, including stroke and carotid artery disease. Techniques in my laboratory allow for in vitro as well as in vivo examination of endothelial responses in blood vessels. We typically examine responses of both large (aorta and carotid artery) and small (pial arterioles) blood vessels in mouse models of hypertension, obesity and diabetes. My interests in vascular biology can be divided into three main research areas:

1) Mechanisms of endothelial dysfunction in mouse models of human hypertension and type II diabetes.
Because type II diabetes accounts for nearly 90% of diabetes in humans and because very little is known regarding vascular responses in type II diabetes we are interested in identifying mechanisms associated with impairment of vascular function in several mouse models of type II diabetes. We have examined mechanisms associated with vascular dysfunction in the db/db mouse and TallyHo mouse, both models of obesity and type II diabetes but of different etiologies (due to leptin receptor deficiency and a mutation in a major diabetes susceptibility locus on chromosome 19, respectively). Because the incidence of obesity is increasing and the most common type of obesity in humans is diet-induced, we are also interested in examining the effects of a high-fat diet on endothelial function. We have obtained data that suggests a high-fat diet is associated with impairment of vascular responses in the cerebral circulation. In addition, mice deficient for gp91phox, a component of the NADPH oxidase (an important source of vascular superoxide) are protected against endothelial dysfunction produced by a high-fat diet. These observations provide the first evidence that endothelium-dependent responses of cerebral vessels are markedly impaired in a mouse model of diet-induced obesity and type II diabetes. These studies are currently funded by an AHA Beginning Grant-In-Aid.
In addition to examination of vascular responses in diabetes, we are also interested in identifying mechanisms associated with vascular dysfunction in hypertension. Using hypertensive double transgenic mice that express both human renin and human angiotensinogen, we have shown that superoxide mediates a large portion of vascular dysfunction associated with this model of angiotensin II-dependent hypertension.

2) Role of superoxide anion and endogenous superoxide dismutases (SOD) in blood vessels.
WThere are three mammalian isoforms of SOD expressed in blood vessels. The three isoforms of SOD are cytosolic or copper-zinc SOD (CuZnSOD or SOD1), manganese SOD (MnSOD or SOD2) localized in mitochondria, and an extracellular form of CuZnSOD (ecSOD or SOD3). All three isoforms catalyze the same reaction:

2H⁺ + 2O^2- → H₂O₂ + O₂

Our studies have primarily focused on the role of CuZnSOD in limiting increases in superoxide and vascular dysfunction because on a percentage basis CuZnSOD accounts for nearly 50-80% of total SOD activity in the vascular wall. Using genetically-altered SOD mice, we found that superoxide levels are increased and vascular dysfunction is present in blood vessels from homozygous CuZnSOD (CuZnSOD-/-)- but not heterozygous CuZnSOD (CuZnSOD+/-) mice. These findings suggest that expression of at least one copy of the gene for CuZnSOD is necessary to protect against increases in superoxide and vascular dysfunction. In addition, we have found that transgenic mice, which overexpress CuZnSOD, are protected against lipopolysaccharide-, ceramide- and angiotensin II-induced increases in superoxide and vascular dysfunction. Ongoing studies in my laboratory are designed to determine whether CuZnSOD protects blood vessels from vascular dysfunction that occurs with aging as well as with the development of obesity and type II diabetes.

3) Role of pro-inflammatory and anti-inflammatory cytokines in limiting increases in superoxide and endothelial dysfunction in response to angiotensin II.
Angiotensin II produces inflammation, oxidative stress and endothelial dysfunction in blood vessels. We are interested in determining whether interleukin 6-deficiency (using IL-6-deficient mice), a pro-inflammatory cytokine, mediates endothelial dysfunction produced by angiotensin II. We have preliminary evidence suggesting that blood vessels from mice deficient in interleukin-6 are protected against endothelial dysfunction produced by angiotensin II.

Honors and Awards

Invited Speaker

Selected Publications

Didion SP, Kinzenbaw DA, Schrader LI, Chu Y, Faraci FM. Endogenous interleukin-10 inhibits angiotensin II-induced vascular dysfunction. Hypertension. Jul 20. [Epub ahead of print],2009.

Modrick ML, Didion SP, Sigmund CD, Faraci FM. Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging. Am J Physiol Heart Circ Physiol. 296:H1914-H1919,2009.

Modrick ML, Didion SP, Lynch CM, Dayal S, Lentz SR, Faraci FM. Role of hydrogen peroxide and the impact of glutathione peroxidase-1 in regulation of cerebral vascular tone. J Cereb Blood Flow Metab. 29:1130-1137,2009.

Didion SP. Chlamydophila pneumoniae and endothelial activation: the smoke that precedes the fire of atherosclerosis? Circulation Research. 102:861-863,2008.

Chrissobolis S, Didion SP, Kinzenbaw DA, Schrader LI, Dayal S, Lentz SR, Faraci FM. Glutathione peroxidase-1 plays a major role in protecting against angiotensin II-induced vascular dysfunction. Hypertension. 51:872-877,2008.

Schrader LI, Kinzenbaw DA, Johnson AW, Faraci FM, Didion SP. IL-6 deficiency protects against angiotensin II induced endothelial dysfunction and hypertrophy. Arterioscler Thromb Vasc Biol. 27:2576-2581,2007.

Brown KA, Didion SP, Andresen JJ, Faraci FM. Effect of aging, MnSOD deficiency, and genetic background on endothelial function: evidence for MnSOD haploinsufficiency. Arterioscler Thromb Vasc Biol. 27:1941-1946,2007.

Didion SP, Lynch CM, Faraci FM. Cerebral vascular dysfunction in TallyHo mice: a new model of Type II diabetes. Am J Physiol Heart Circ Physiol. 292:H1579-H1583,2007.

Didion SP, Kinzenbaw DA, Schrader LI, Faraci FM. Heterozygous CuZn superoxide dismutase deficiency produces a vascular phenotype with aging. Hypertension. 48:1072-1079,2006.

Baumbach GL, Didion SP, Faraci FM. Hypertrophy of cerebral arterioles in mice deficient in expression of the gene for CuZn superoxide dismutase. Stroke. 37:1850-1855,2006.

Faraci FM, Modrick ML, Lynch CM, Didion LA, Fegan PE, Didion SP. Selective cerebral vascular dysfunction in Mn-SOD-deficient mice. J Appl Physiol. 100:2089-2093,2006.

Faraci FM, Lamping KG, Modrick ML, Ryan MJ, Sigmund CD, Didion SP. Cerebral vascular effects of angiotensin II: new insights from genetic models. J Cereb Blood Flow Metab. 26:449-455, 2006.

Didion SP, Kinzenbaw DA, Faraci FM. Critical role for CuZn-superoxide dismutase in preventing angiotensin II-induced endothelial dysfunction. Hypertension. 46:1147-1153,2005.

Didion SP, Lynch CM, Baumbach GL, Faraci FM. Impaired endothelium-dependent responses and enhanced influence of Rho-kinase in cerebral arterioles in type II diabetes. Stroke. 36:342-347,2005.

Didion SP, Faraci FM. Ceramide-induced impairment of endothelial function is prevented by CuZn superoxide dismutase overexpression. Arterioscler Thromb Vasc Biol. 25:90-95,2005.

Didion SP, Kinzenbaw DA, Fegan PE, Didion LA, Faraci FM. Overexpression of CuZn-SOD prevents lipopolysaccharide-induced endothelial dysfunction. Stroke. 35:1963-1967,2004.

Faraci FM, Didion SP. Vascular protection: superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol. 24:1367-1373,2004.

Ryan MJ, Didion SP, Mathur S, Faraci FM, Sigmund CD. Angiotensin II-induced vascular dysfunction is mediated by the AT1A receptor in mice. Hypertension. 43:1074-1079,2004.

Ryan MJ, Didion SP, Mathur S, Faraci FM, Sigmund CD. PPAR(gamma) agonist rosiglitazone improves vascular function and lowers blood pressure in hypertensive transgenic mice. Hypertension. 43:661-666,2004.

Didion SP, Faraci FM. Angiotensin II produces superoxide-mediated impairment of endothelial function in cerebral arterioles. Stroke. 34:2038-2042,2003.

Didion SP, Ryan MJ, Didion LA, Fegan PE, Sigmund CD, Faraci FM. Increased superoxide and vascular dysfunction in CuZnSOD-deficient mice. Circulation Research. 91:938-944,2002.

Didion SP, Ryan MJ, Baumbach GL, Sigmund CD, Faraci FM. Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen. Am J Physiol Heart Circ Physiol. 283:H1569-H1576,2002.

Ryan MJ, Didion SP, Davis DR, Faraci FM, Sigmund CD. Endothelial dysfunction and blood pressure variability in selected inbred mouse strains. Arterioscler Thromb Vasc Biol. 22:42-8,2002.

Didion SP, Faraci FM. Effects of NADH and NADPH on superoxide levels and cerebral vascular tone. Am J Physiol Heart Circ Physiol. 282:H688-95,2002.

Didion SP, Hathaway CA, Faraci FM. Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD. Am J Physiol Heart Circ Physiol. 281:H1697-703,2001.

Didion SP, Heistad DD, Faraci FM. Mechanisms that produce nitric oxide-mediated relaxation of cerebral arteries during atherosclerosis. Stroke. 32:761-766, 2001.

Didion SP, Sigmund CD, Faraci FM. Impaired endothelial function in transgenic mice expressing both human renin and human angiotensinogen. Stroke. 31:760-764, 2000.

Education and Training

Research Experience & Academic Appointments

Society Memberships