Abnormal endothelial function plays a key role in the pathophysiology of several vascular diseases. The overall theme of this Program is mechanisms of endothelial dysfunction in atherosclerosis and hypertension, with emphasis on the balance between oxidative and antioxidant mechanisms, and between inflammation and anti-inflammatory mechanisms. Better understanding of oxidative injury and inflammation will be needed before these exciting areas of research can be translated into effective treatment for atherosclerosis and other vascular diseases. Studies are proposed to examine several novel hypotheses. The goals are tightly focused and cohesive. First, angiotensin II may contribute to hypertension, in substantial part by oxidative and inflammatory mechanisms. Second, interleukin-10 is an important anti-inflammatory cytokine which may protect against vascular disease, including hypertension. Third, an innate immune response may be generated by non-macrophage vascular cells, and transduce immune responses to several inflammatory mediators. Fourth, impairment of antioxidant mechanisms, including extracellular and manganese superoxide dismutases, may be of great importance in vascular disease. Fifth, accelerated thrombosis in atherosclerotic mice is produced by oxidative inactivation of thrombomodulin and decreased activation of the anticoagulant protein C. Sixth, peroxisome proliferator activated receptor gamma may modulate vascular function and atherogenesis through activation and repression of target genes in the blood vessel wall. The Program consists of four projects and an administration core, which includes a bioinformatics section. The investigators integrate pharmacological approaches, state-of-the-art molecular approaches, sophisticated physiological measurements in mice, and novel genetically altered mice in each project. There is a sustained record of excellent productivity, with close collaboration among the investigators within an outstanding environment. The long-term goal of the Program is to contribute to better understanding of oxidative and inflammatory mechanisms of vascular diseases, to allow translation into improved treatment of atherosclerosis and other vascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Wassef, Momtaz K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
Zip Code
Doddapattar, Prakash; Jain, Manish; Dhanesha, Nirav et al. (2018) Fibronectin Containing Extra Domain A Induces Plaque Destabilization in the Innominate Artery of Aged Apolipoprotein E-Deficient Mice. Arterioscler Thromb Vasc Biol 38:500-508
Hu, Xiaoming; De Silva, T Michael; Chen, Jun et al. (2017) Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke. Circ Res 120:449-471
De Silva, T Michael; Hu, Chunyan; Kinzenbaw, Dale A et al. (2017) Genetic Interference With Endothelial PPAR-? (Peroxisome Proliferator-Activated Receptor-?) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1-7. Hypertension 70:559-565
Dhanesha, Nirav; Doddapattar, Prakash; Chorawala, Mehul R et al. (2017) ADAMTS13 Retards Progression of Diabetic Nephropathy by Inhibiting Intrarenal Thrombosis in Mice. Arterioscler Thromb Vasc Biol 37:1332-1338
Chen, Zixin; Li, Yongjun; Yu, Hong et al. (2017) Isolation of Extracellular Vesicles from Stem Cells. Methods Mol Biol 1660:389-394
Shinohara, Keisuke; Liu, Xuebo; Morgan, Donald A et al. (2016) Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension. Hypertension 68:1385-1392
Ketsawatsomkron, Pimonrat; Keen, Henry L; Davis, Deborah R et al. (2016) Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator-Activated Receptor-? Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate-Salt Hypertension. Hypertension 67:214-22
Chu, Yi; Lund, Donald D; Doshi, Hardik et al. (2016) Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice. Arterioscler Thromb Vasc Biol 36:466-74
Hu, Chunyan; Lu, Ko-Ting; Mukohda, Masashi et al. (2016) Interference with PPAR? in endothelium accelerates angiotensin II-induced endothelial dysfunction. Physiol Genomics 48:124-34
Gu, Sean X; Blokhin, Ilya O; Wilson, Katina M et al. (2016) Protein methionine oxidation augments reperfusion injury in acute ischemic stroke. JCI Insight 1:

Showing the most recent 10 out of 288 publications