Ischemia/reperfusion (I/R) induces leukoeyte/endothelial cell adhesive interactions (LECA) in postcapillary venules and impaired endothelium-dependent, NO-mediated vasodllatory responses (EDD) in upstream arterioles. Even though leukocytes do not roll along, adhere to, or emigrate across arteriolar endothelium in postischemic intestine, recent work indicates that l/R-induced venular LECA is causally linked to EDD in arterioles. However, the mechanisms coupling l/R-induced postcapillary venular LECA and EDD in upstream arterioles are unknown. Our overall hypothesis is that l/R-induced EDD in arterioles occurs by a mechanism that is triggered by LECA in postcapillary venules and involves the formation of signals in the interstitium elicited by the proteolytic activity of emigrated leukocytes which exposes matricryptic sites in the extracellular matrix (ECM) that interact with the integrin avp3 to induce mast cell-dependent formation of angiotensin II (Ang II). Subsequent activation of NAD(P)H oxidase promotes eNOS uncoupling in the vascular wall and leads to the formation of oxidants which inactivate NO, resulting in arteriolar EDD.
Our Specific Aims are to determine:
Aim A) whether venular LECA play an obligatory role in the development of EDD in upstream arterioles;
Aim B) the contribution of leukocyte-derived proteases to the development of arteriolar EDD;
Aim C) the role of avp3 integrin in initiating chymase-dependent formafion of Ang II;
and Aim D) the role of Ang ll-dependent, NAD(P)H oxidase- and uncoupled eNOS-mediated oxidant production in arteriolar EDD. Intravital microscopic approaches will be used to examine arteriolar EDD, venular LECA, and mast cell responses to I/R. Arterioles will be isolated from non-ischemic intesfine and exposed to posfischemic lymph, as a means to examine interstitial signals that are generated by the proteolytic acfivity of extravasated leukocytes. A novel three-dimensional ECM model engrafted with isolated cannulated arterioles and seeded with mast cells in the presence and absence of neutrophils will also be used to to further explore our hypothesis. Isolated arterioles obtained from a number of gene knockout and transgenic animal models will be used to further explore the mechanisms of arteriolar EDD. Collectively, these aims address a novel mechanism to explain the profound disturbance in arteriolar vasoregulatory funcfion in postischemic tissues. Significance: This work will identify new links between LECA in postcapillary venules, signals generated in the interstitium by emigrated leukocytes, and EDD in arterioles. Given the importance of the endothelium in regulating vascular tone, these fundamentally important findings have enormous implications for our understanding of blood flow dysregulation in conditions characterized by I/R.

Public Health Relevance

Reductions in the blood supply (ischemia) to the heart, brain, kidneys, or intestine are major causes of death and disability. As a result of ischemia, arterial blood vessels become dysfunctional and unable to regulate their diameter. The goal of this project is to identify the cells and molecular pathways involved in the pathogenesis of arterial dysfunction after ischemia for design of new therapeutic approaches for treatment.

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)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Missouri-Columbia
United States
Zip Code
Manrique, Camila; Habibi, Javad; Aroor, Annayya R et al. (2016) Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice. Cardiovasc Diabetol 15:94
Foote, Christopher A; Castorena-Gonzalez, Jorge A; Staiculescu, Marius C et al. (2016) Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization. Am J Physiol Heart Circ Physiol 310:H188-98
Wang, Derek Z; Jones, Allan W; Wang, Walter Z et al. (2016) Soluble guanylate cyclase activation during ischemic injury in mice protects against postischemic inflammation at the mitochondrial level. Am J Physiol Gastrointest Liver Physiol 310:G747-56
Higashi, Yusuke; Sukhanov, Sergiy; Shai, Shaw-Yung et al. (2016) Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E-Deficient Mice. Circulation 133:2263-78
Sehgel, Nancy L; Sun, Zhe; Hong, Zhongkui et al. (2015) Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging. Hypertension 65:370-7
Scallan, Joshua P; Hill, Michael A; Davis, Michael J (2015) Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling. Cardiovasc Res 107:89-97
Dudenbostel, Tanja; Acelajado, Maria C; Pisoni, Roberto et al. (2015) Refractory Hypertension: Evidence of Heightened Sympathetic Activity as a Cause of Antihypertensive Treatment Failure. Hypertension 66:126-33
Nance, Michael E; Whitfield, Justin T; Zhu, Yi et al. (2015) Attenuated sarcomere lengthening of the aged murine left ventricle observed using two-photon fluorescence microscopy. Am J Physiol Heart Circ Physiol 309:H918-25
Fairfax, Seth T; Padilla, Jaume; Vianna, Lauro C et al. (2015) Myogenic responses occur on a beat-to-beat basis in the resting human limb. Am J Physiol Heart Circ Physiol 308:H59-67
Zuidema, Mozow Y; Korthuis, Ronald J (2015) Intravital microscopic methods to evaluate anti-inflammatory effects and signaling mechanisms evoked by hydrogen sulfide. Methods Enzymol 555:93-125

Showing the most recent 10 out of 48 publications