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.
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