Acute inflammation is characterized by increased microvascular permeability to plasma proteins and leukocyte recruitment into inflammatory sites. A large increase in permeability of the microvessel wall is a critical event resulting in edema formation and organ dysfunction. The long-term goal of our research is to investigate the mechanisms that regulate microvessel permeability under inflammatory conditions. The objective of this proposal is to investigate the direct correlation between vascular structural changes, transport pathway formations, signal transduction pathways, and the magnitude and time course of the permeability changes in intact microvessels in response to different stimuli.
Three specific aims are proposed: 1) Investigate the cellular mechanisms of endothelial gap formation and inflammatory mediator-induced permeability increases in intact microvessels under acute and chronic inflammatory conditions;2) Investigate the role of pericytes and the basement membranes in the regulation of microvessel permeability under acute and chronic inflammatory conditions;and 3) Identify the cellular mechanisms responsible for ROS-induced permeability increases under acute and chronic inflammatory conditions.
These aims will be accomplished using combined confocal microscopy, electron microscopy, with quantitative assessments of microvessel permeability in intact microvessels. Our newly established methods enable us to three- dimensionally visualize and quantify inflammatory mediator-induced gap formation, characterize the changes in endothelial adhesion proteins, as well as to detect changes in actin cytoskeleton in endothelial cells and pericytes in individually perfused microvessels. The electron microscopy study allows ultrastructural changes to be correlated with confocal image findings. The proposed research will provide new information and possibly new concept for a better understanding of the mechanisms that regulate fluid and solute transport when permeability is increased under inflammatory conditions. The insight gained will be directly applied to the identification of an effective target to prevent the permeability increase and contribute to the development of targeted and clinically applicable anti-inflammatory therapies.
The long-term goal of our research is to investigate the cellular mechanisms that regulate permeability in intact microvessels. Accumulated clinical and experimental evidence indicate that an inflammation-associated increase in vascular permeability is the initiating event for a variety of cardiovascular diseases (such as atherosclerosis, diabetes) as well as promoting tumor growth and tumor metastasis. A better understanding of the mechanisms that regulate microvessel permeability is crucial to defining the pathogenesis of many disease conditions, and to aid in the development of novel therapeutic approaches.
|Li, Xiang; Xu, Sulei; He, Pingnian et al. (2015) In vitro recapitulation of functional microvessels for the study of endothelial shear response, nitric oxide and [Ca2+]i. PLoS One 10:e0126797|
|Yuan, Dong; Xu, Sulei; He, Pingnian (2014) Enhanced permeability responses to inflammation in streptozotocin-induced diabetic rat venules: Rho-mediated alterations of actin cytoskeleton and VE-cadherin. Am J Physiol Heart Circ Physiol 307:H44-53|
|Xu, Sulei; Zhou, Xueping; Yuan, Dong et al. (2013) Caveolin-1 scaffolding domain promotes leukocyte adhesion by reduced basal endothelial nitric oxide-mediated ICAM-1 phosphorylation in rat mesenteric venules. Am J Physiol Heart Circ Physiol 305:H1484-93|
|Zhou, Xueping; Yuan, Dong; Wang, Mingxia et al. (2013) H2O2-induced endothelial NO production contributes to vascular cell apoptosis and increased permeability in rat venules. Am J Physiol Heart Circ Physiol 304:H82-93|
|Yuan, Dong; He, Pingnian (2012) Vascular remodeling alters adhesion protein and cytoskeleton reactions to inflammatory stimuli resulting in enhanced permeability increases in rat venules. J Appl Physiol 113:1110-20|
|Zhou, Xueping; He, Pingnian (2011) Improved measurements of intracellular nitric oxide in intact microvessels using 4,5-diaminofluorescein diacetate. Am J Physiol Heart Circ Physiol 301:H108-14|
|Zhou, Xueping; He, Pingnian (2011) Temporal and spatial correlation of platelet-activating factor-induced increases in endothelial [CaÂ²âº]i, nitric oxide, and gap formation in intact venules. Am J Physiol Heart Circ Physiol 301:H1788-97|
|Zhang, Gengqian; Xu, Sulei; Qian, Yan et al. (2010) Sphingosine-1-phosphate prevents permeability increases via activation of endothelial sphingosine-1-phosphate receptor 1 in rat venules. Am J Physiol Heart Circ Physiol 299:H1494-504|
|He, Pingnian (2010) Leucocyte/endothelium interactions and microvessel permeability: coupled or uncoupled? Cardiovasc Res 87:281-90|
|Zhou, Xueping; He, Pingnian (2010) Endothelial [Ca2+]i and caveolin-1 antagonistically regulate eNOS activity and microvessel permeability in rat venules. Cardiovasc Res 87:340-7|