The overall aim of this research is to investigate the role of the circulating hormones known as Natriuretic Peptides (NPs) as endogenous anti-inflammatory agents that reduce vascular hyperpermeability in intact microvessels and tissues that have been exposed to inflammation. Previous investigations of the role of NPs to modify vascular permeability in intact tissues and whole animals focused on physiological functions of NPs that increase vascular permeability and control vascular volume in normal (non-inflamed) conditions. We will test the idea that action of NPs to increase or decrease vascular permeability depends on the endothelial phenotype. Key observations from our laboratory are that the difference between conditions where NPs reduce permeability and conditions where NPs increase permeability is the presence or absence of upregulated contractile mechanisms in endothelial cells. For example, most investigations showing that NPs reduce permeability are in cultured endothelial monolayers. In these monolayers the inflammatory mediator thrombin is a robust activator of contractile mechanisms and NPs reduce the thrombin induced contractile force and attenuate the formation of large paracellular gaps. On the other hand, microvessels where NPs increase permeability do not respond to thrombin and permeability is low because strong adhesion forces maintain tight intercellular junctions. We propose experiments to induce the contractile phenotype in microvessels and tissues, which initially express the strong adhesion phenotype, by exposing them to inflammatory conditions. We will then use the expertise of our laboratory to study the regulation of vascular permeability at the cellular, single vessel, and whole organ levels. We will use the results from experiments in cultured endothelial monolayers to guide the design and interpretation of these investigations. The overall hypothesis is that the action of NPs to regulate vascular permeability depends on the endothelial phenotype. The phenotype determines activity of cGMP dependent phosphodiesterases to modulate endothelial cAMP and cGMP levels and the activity of their downstream effectors to modify both cell-cell adhesion and contractile mechanisms.
Specific Aim 1 tests the hypothesis that NPs attenuate increased permeability only when contractile mechanisms are up-regulated in microvessels.
Specific Aim 2 tests the hypothesis that cellular mechanisms investigated in cultured endothelial cells regulate NP dependent decreases of vascular hyperpermeability.
Specific Aim 3 tests the hypothesis that NPs attenuation of contractile mechanisms is sufficient to reduce hyperpermeability and accelerate wound healing in a new mouse skin wound model. At the completion of these Specific Aims we expect to provide the first systematic evaluation of NP actions to reduce hyperpermeability in intact tissue exposed to inflammation. This provides new knowledge of the different mechanisms modulating vascular permeability in intact tissue, and is a step towards better knowledge of the conditions where NPs may improve clinical outcomes by their action to attenuate hyperpermeability.

Public Health Relevance

Natriuretic peptides are normally present at very low levels in the circulating plasma and are part of physiological systems that control plasma volume. During diseases such as heart failure and sepsis, circulating levels of natriuretic peptides increase and are used as biomarkers of the severity of disease. On the other hand natriuretic peptides may also be infused after myocardial infarction to improve outcomes. We will investigate the idea that under conditions of inflammation and tissue injury, natriuretic peptides act on endothelial cells that express a pro-inflammatory phenotype to limit increases in vascular permeability that would otherwise compromise organ function, but still allow active immune responses. Understanding this fine tuning of hyperpermeability by natriuretic peptides may improve the management of disease states with elevated natriuretic peptides.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL028607-32
Application #
8692561
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Charette, Marc F
Project Start
Project End
Budget Start
Budget End
Support Year
32
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Davis
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Davis
State
CA
Country
United States
Zip Code
95618
Morikis, Vasilios A; Radecke, Chris; Jiang, Yanyan et al. (2016) Atrial natriuretic peptide down-regulates neutrophil recruitment on inflamed endothelium by reducing cell deformability and resistance to detachment force. Biorheology 53:109
Zhang, Lin; Zeng, Min; Fan, Jie et al. (2016) Sphingosine-1-phosphate Maintains Normal Vascular Permeability by Preserving Endothelial Surface Glycocalyx in Intact Microvessels. Microcirculation 23:301-10
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Morikis, Vasilios A; Radecke, Chris; Jiang, Yanyan et al. (2015) Atrial natriuretic peptide down-regulates neutrophil recruitment on inflamed endothelium by reducing cell deformability and resistance to detachment force. Biorheology 52:447-63
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Adamson, R H; Sarai, R K; Altangerel, A et al. (2013) Microvascular permeability to water is independent of shear stress, but dependent on flow direction. Am J Physiol Heart Circ Physiol 304:H1077-84

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