Results:Gremlin-1 binds with high affinity to macrophage migration inhibitory factor and attenuates the progression of atherosclerosis. Conclusion:We describe a novel mechanism that regulates foam cell formation and plaque growth. Significance: The findings disclose a new mechanism for the regulation of plaque growth and may open novel therapeutic strategies to control the progression of atherosclerosis.Monocyte infiltration and macrophage formation are pivotal steps in atherosclerosis and plaque vulnerability. Gremlin-1/ Drm is crucial in embryo-/organogenesis and has been shown to be expressed in the adult organism at sites of arterial injury and to inhibit monocyte migration. The purpose of the present study was to evaluate and characterize the role of Gremlin-1 in atherosclerosis. Here we report that Gremlin-1 is highly expressed primarily by monocytes/macrophages in aortic atherosclerotic lesions of ApoE Atherosclerosis is a chronic disease of the arteries characterized by inflammation of the vessel wall (1-3). Endothelial activation, monocyte recruitment, and the formation of macrophages are critical events in the development of atherosclerosis (4). Macrophages secrete cytokines/chemokines and growth factors that promote atheroprogression and contribute substantially to plaque vulnerability and acute complications of the disease such as acute coronary syndromes (5). The cytokine macrophage migration inhibitory factor (MIF) 2 is a noncognate ligand of CXC chemokine receptors and regulates monocyte recruitment toward atherosclerotic lesions (6). Blocking or genetic deletion of MIF reduces macrophage and T-cell content of atherosclerotic plaques and attenuates the progression of atherosclerosis in ApoE Ϫ/Ϫ mice (7). Gremlin-1 and its rat homolog Drm (down-regulated by v-mos) are highly conserved 20.7-kDa glycoproteins (8, 9). Gremlin-1 belongs to the DAN/Cerberus protein family, which is a member of the cysteine knot superfamily that includes TGF-␤ and VEGF (10). Gremlin-1 is a bone morphogenetic protein (BMP) antagonist and binds to BMP-2, -4, and -7 (9). It exists in secreted and cell-associated forms (9). The Gremlin-1 gene encodes a 23-and 28-kDa protein that is glycosylated before secretion (9). Gremlin-1-dependent inhibition of BMPs is important for embryogenesis and development of organs such as limbs, kidney, and lungs (11, 12). Gremlin-1 knock-out mice are neonatally lethal with significant renal and lung defects (13). Transgenic mice overexpressing Gremlin-1 under the control of the osteocalcin promoter show reduced bone formation (14). Gremlin-1 is expressed in endothelial cells exposed to disturbed flow in mouse aorta and in human coro-

Key Points PLTs contribute to apoptosis in vivo and express the death receptor ligand FasL upon activation. Membrane-bound FasL mediates PLT-induced apoptosis, whereas Bax/Bak signaling is not required but reinforces PLT-induced apoptosis.

Mechanisms that limit thrombosis are poorly defined. One of the few known endogenous platelet inhibitors is nitric oxide (NO). NO activates NO sensitive guanylyl cyclase (NO-GC) in platelets, resulting in an increase of cyclic guanosine monophosphate (cGMP). Here we show, using cGMP sensor mice to study spatiotemporal dynamics of platelet cGMP, that NO-induced cGMP production in pre-activated platelets is strongly shear-dependent. We delineate a new mode of platelet-inhibitory mechanotransduction via shear-activated NO-GC followed by cGMP synthesis, activation of cGMP-dependent protein kinase I (cGKI), and suppression of Ca2+ signaling. Correlative profiling of cGMP dynamics and thrombus formation in vivo indicates that high cGMP concentrations in shear-exposed platelets at the thrombus periphery limit thrombosis, primarily through facilitation of thrombus dissolution. We propose that an increase in shear stress during thrombus growth activates the NO-cGMP-cGKI pathway, which acts as an auto-regulatory brake to prevent vessel occlusion, while preserving wound closure under low shear.

Many pathophysiological processes are associated with proliferation, migration or death of distinct cell populations. Monitoring specific cell types and their progeny in a non-invasive, longitudinal and quantitative manner is still challenging. Here we show a novel cell-tracking system that combines Cre/lox-assisted cell fate mapping with a thymidine kinase (sr39tk) reporter gene for cell detection by positron emission tomography (PET). We generate Rosa26-mT/sr39tk PET reporter mice and induce sr39tk expression in platelets, T lymphocytes or cardiomyocytes. As proof of concept, we demonstrate that our mouse model permits longitudinal PET imaging and quantification of T-cell homing during inflammation and cardiomyocyte viability after myocardial infarction. Moreover, Rosa26-mT/sr39tk mice are useful for whole-body characterization of transgenic Cre mice and to detect previously unknown Cre activity. We anticipate that the Cre-switchable PET reporter mice will be broadly applicable for non-invasive long-term tracking of selected cell populations in vivo.