The goals of this research program are to elucidate the mechanisms that govern the cardiovascular response during hemorrhagic shock and to identify new therapeutic targets for trauma patients. Our previous work and new preliminary data suggest that activation of CXC chemokine receptor (CXCR) 7 results in vascular catecholamine resistance and cardiovascular collapse, whereas CXCR4 activation maintains vascular reactivity to catecholamines during hemorrhagic shock. This leads to the main hypothesis that CXCR4 and CXCR7 are critical regulators of cardiovascular function during hemorrhagic shock, which influence vascular tone through modulation of adrenergic receptor (AR) signaling. To test our hypothesis, we propose the following aims: 1. To determine how pharmacological CXCR4/7 modulation affect vascular function ex vivo. Utilizing pressure myography as a test platform, we will answer the following key questions: Are the effects of CXCR4/7 agonists on vascular reactivity specific for ?1AR activation? Are there differences among vascular beds? Does the endothelium contribute to the observed effects? Can effects of SDF-1? on CXCR4 and CXCR7 be differentiated? How does uncoupling of G?i protein affect the actions of CXCR4/7 modulators? Does hemorrhagic shock induce persistent changes in vascular reactivity? 2. To determine how CXCR4/7 influence cardiovascular function during catecholamine exposure and hemorrhagic shock in vivo. We will utilize pressure volume loop analyses to determine how CXCR4/7 modulation alters cardiovascular function in response to adrenergic agonists and during hemorrhagic shock with subsequent fluid resuscitation. Furthermore, we will determine whether deleterious effects of CXCR7 on normal cardiovascular function can be rescued, test whether animals with prolonged survival after CXCR4 activation during otherwise lethal hemorrhagic shock can be rescued from cardiovascular collapse with fluid resuscitation and evaluate long term consequences of selective CXCR4 activation during shock and resuscitation. 3. To identify the molecular mechanisms underlying vascular effects of CXCR4/7. The specific hypothesis is that CXCR4/7 control ?1AR signaling. To test this hypothesis, we will determine the mechanism of cross-talk between CXCR4/7/?1AR, the mechanism of their signaling crosstalk and elucidate the pathway by which CXCR4/7 modulate ?1AR-induced vasoconstriction in vascular smooth muscle cells. We propose a comprehensive series of state-of-the-art in vivo and ex vivo studies complemented with biochemical, molecular and cellular biology approaches to elucidate the molecular mechanisms by which CXCR4 and CXCR7 modulate ?1AR signaling to control vascular tone during hemorrhagic shock. New knowledge gained from this proposal will help to establish CXCR4/7 as drug targets to stabilize cardiovascular function and enhance shock tolerance.
In this project, we will establish a new aspect on the regulation of cardiovascular function during hemorrhagic shock: the regulation of vascular function by CXC chemokine receptors 4 and 7. The knowledge gained from this research is expected to provide new therapeutic targets to improve cardiovascular function during the stress response. This could lead to improved treatment strategies for trauma patients and also for a broad variety of other diseases, in which cardiovascular function is impaired.
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