Domenick J. Falcone   Associate Professor of Pathology and Laboratory Medicine


Macrophage Proteinases and Vascular Remodeling

Research in the laboratory is primarily focused on the mechanisms by which macrophages contribute to the pathogenesis and progression of atherosclerosis and aneurysmal dilation. Complications of these chronic vascular diseases remain a major cause of morbidity and mortality in the United States. Current studies seek to understand how matrix metalloproteinases (MMPs) and clyclooxygenase-2 (COX-2)-derived prostanoids collaborate to induce macrophages to undermine the structural integrity of the artery wall. MMPs are a large family of neutral endopeptidases that participate in diverse physiologic and pathologic processes. The degradation of extracellular matrix components is commonly thought to be the principal mechanism by which MMPs regulate these diverse biological processes. However, it has become clear that in addition to degrading extracellular matrix components, MMPs regulate the immune response, cell migration, and growth and development via their ability to modify the activities of protease activated receptors, proteinase inhibitors, cytokines, chemokines and growth factors. Genetic models have revealed that MMP-9 (type IV collagenase) expression plays a casual role in atherosclerotic lesion development and aneurysmal dilation. MMP-9 expression, absent in normal arteries, is markedly up-regulated in vascular lesions due to the recruitment of large numbers of macrophages. Utilizing pharmacologic and genetic approaches, we have demonstrated that macrophage MMP-9 expression induced by a variety of inflammatory stimuli is dependent on increased COX-2 expression, subsequent prostaglandin E2 (PGE2) synthesis and PGE2 binding to EP4 #150; a member of the PGE2 receptor family. Ongoing projects in the laboratory seek to (1) unravel the complex signaling pathways by which MMPs and cytokines commonly found in inflammatory settings regulate the COX-2 - PGE2 - EP4 axis; and (2) determine whether selective targeting of EP4 in vivo has a therapeutic advantage over COX-2 inhibitors in blocking MMP-9 expression and stabilizing atherosclerotic and aneurysmal lesions.



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Grants awarded

  • PGE2 Receptors as Therapeutic Targets in Occlusive and Aneury Small Vascular Disease  awarded by National Heart, Lung, & Blood Institute Principal Investigator 2010 -
  • Doxycycline for COPD in HIV-Infected Patients  awarded by National Heart, Lung, & Blood Institute Key Personnel 2012 - 2016



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