Increased microvascular permeability is a hallmark of inflammation. Previous research has focused on how to prevent the onset and the maintenance of the elevated permeability under inflammatory conditions. . We propose to test the central hypothesis that Microvascular permeability is regulated by counterbalancing signaling mechanisms that maintain homeostasis by enhancing permeability or barrier properties, respectively. We will investigate eNOS translocation as a mechanism that stimulates hyperpermeability and mechanisms that inactivate hyperpermeability in the early inflammatory phase. We will study these processes in endothelial cells and in striated muscle. We hypothesize that eNOS translocation is necessary to achieve effective NO concentrations at or near the effectors for permeability. We also hypothesize that at or near the peak of the hyperpermeability response, the endothelium (or tissue) begins a process to inactivate or reverse hyperpermeability and restore the physiological barrier properties of the microvascular wall. We further propose that the small GTP-binding proteins Epac/Rap-1 serve as `Barrier Enhancing Factors'and participate in the hyperpermeability-inactivation/reversal process. The Specific Hypotheses and Specific Aims to be tested are: SPECIFIC HYPOTHESIS 1. eNOS translocation to cytosol (non-Golgi cytosol compartment) is a step in endothelial regulation of microvascular permeability.
SPECIFIC AIM 1. To investigate the relationship between eNOS translocation and regulation of endothelial and microvascular permeability. SPECIFIC HYPOTHESIS 2: cAMP via Epac inactivates or reverses agonist-induced hyperpermeability.
SPECIFIC AIM 2. 1 To investigate the timed inactivation/reversal of hyperpermeability.
SPECIFIC AIM 2. 1. To determine whether or not stimulation of Epac reverses (inactivates) agonist-induced hyperpermeability. We will apply intravital microscopy in conjunction with computer-assisted image analysis and molecular biology approaches to elucidate the postulated mechanisms.
A better understanding of the molecular mechanisms and of the timing between hyperpermeability and its """"""""physiological"""""""" inactivation or reversal in inflammatory processes should provide a window of opportunity for promoting inactivation or reversal of hyperpermeability to prevent complications such as excessive edema and compartment syndrome in (micro)vascular disease.
|DurÃ¡n, Walter N; SÃ¡nchez, Fabiola A (2016) New Member of Endothelial Arsenal Against Inflammation. Circ Res 119:178-80|
|Duran, Walter N; Beuve, Annie V; Sanchez, Fabiola A (2013) Nitric oxide, S-nitrosation, and endothelial permeability. IUBMB Life 65:819-26|
|Figueroa, Xavier F; GonzÃ¡lez, Daniel R; Puebla, Mariela et al. (2013) Coordinated endothelial nitric oxide synthase activation by translocation and phosphorylation determines flow-induced nitric oxide production in resistance vessels. J Vasc Res 50:498-511|
|Marin, Natalie; Zamorano, Patricia; Carrasco, Rodrigo et al. (2012) S-Nitrosation of Ã½Ã½-catenin and p120 catenin: a novel regulatory mechanism in endothelial hyperpermeability. Circ Res 111:553-63|
|Crassous, Pierre-Antoine; Couloubaly, Samba; Huang, Can et al. (2012) Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model. Am J Physiol Heart Circ Physiol 303:H597-604|
|Sanchez, Fabiola A; Rana, Roshniben; Gonzalez, Francisco G et al. (2011) Functional significance of cytosolic endothelial nitric-oxide synthase (eNOS): regulation of hyperpermeability. J Biol Chem 286:30409-14|
|Duran, Walter N; Breslin, Jerome W; Sanchez, Fabiola A (2010) The NO cascade, eNOS location, and microvascular permeability. Cardiovasc Res 87:254-61|
|Kim, David D; Kleinman, David M; Kanetaka, Takehito et al. (2010) Rapamycin inhibits VEGF-induced microvascular hyperpermeability in vivo. Microcirculation 17:128-36|
|Sanchez, Fabiola A; Rana, Roshniben; Kim, David D et al. (2009) Internalization of eNOS and NO delivery to subcellular targets determine agonist-induced hyperpermeability. Proc Natl Acad Sci U S A 106:6849-53|
|Kim, David D; Kanetaka, Takehito; Duran, Ricardo G et al. (2009) Independent regulation of periarteriolar and perivenular nitric oxide mechanisms in the in vivo hamster cheek pouch microvasculature. Microcirculation 16:323-30|
Showing the most recent 10 out of 22 publications