Monocyte-derived macrophages play a critical role in initiation and progression of atherosclerotic plaques. The investigators have demonstrated that monocytes are preferentially recruited to arterial areas susceptible to lipoprotein deposition and lesion formation. Monocyte recruitment is controlled by a series of events involving recognition of endothelial cell (EC), leukocyte adhesion molecules and cell- and lipoprotein-derived monocyte chemotactic factors. However, it remains questionable whether recruitment from the blood is, by itself, sufficient to explain the large numbers of macrophages in early lesions. Once recruited, macrophages sequester lipid via uptake of modified and oxidized LDL and become foam cells. The investigators and others have suggested a protective lipid clearance role of the monocyte in early atherogenesis. Whether its role is pro- or anti-atherogenic, mechanisms which significantly alter numbers or lipoprotein metabolism of macrophages could have major impact on lesion progression. Preliminary studies from the investigator's lab have shown that monocytes can be induced to significant, prolonged proliferation via an EC-specific, contact-dependent mechanism distinct from but synergistic with the action of MCSF. This mechanism appears to be regulated via the avb3 and avb5 integrins. Moreover, monocytes in contact with EC show identical scavenger receptor-mediated uptake of acetyl-LDL as monocytes on plastic, but do not accumulate lipid and form foam cells, as do the latter. Rather, they export scavenged cholesterol to an acceptor protein released into the medium. The investigators hypothesize that EC may regulate both differentiation of monocytes into a proliferative phenotype as well as their metabolism and clearance of scavenged lipid. The objectives of the proposed studies are to elucidate mechanism of EC contact-induced differentiation of monocytes, define mechanisms by which EC regulate these functions, and examine the effect of known atherogenic stimuli on EC regulation of monocyte differentiation and function.
Three specific aims are proposed, namely 1) To test the hypothesis that the contact-dependent mechanism of regulation of monocyte proliferation by EC involves signaling via avb3 and avb5 integrins, which act synergistically with the monocytes MCSF receptor to control cell cycle regulatory proteins. 2) To test the hypothesis that the mechanism by which EC inhibit macrophage lipid accumulation is by regulating Mf lipoprotein degradation, cholesterol esterification, ACAT activity and reverse transport 3) To test the hypothesis that contact with EC modulates the effects of atherogenic lipoproteins on monocyte proliferation and terminal differentiation.
| Orfanos, S E; Parkerson, J B; Chen, X et al. (2000) Reduced lung endothelial angiotensin-converting enzyme activity in Watanabe hyperlipidemic rabbits in vivo. Am J Physiol Lung Cell Mol Physiol 278:L1280-8 |
