Huanhuan He1, Julia J Mack1, Esra Güç1, Carmen M Warren1, Mario Leonardo Squadrito1, Witold W Kilarski1, Caroline Baer1, Ryan D Freshman1, Austin I McDonald1, Safiyyah Ziyad1, Melody A Swartz1, Michele De Palma1, M Luisa Iruela-Arispe2. 1. From the Department of Human Genetics (H.H.), Department of Molecular, Cell and Developmental Biology (J.J.M., C.M.W., R.D.F., A.I.M., S.Z., M.L.I.-A.), Molecular Biology Institute (M.L.I.-A.), and Jonsson Comprehensive Cancer Center (M.L.I.-A.), University of California, Los Angeles; Institute for Bioengineering (IBI) (E.G., M.A.S.) and The Swiss Institute for Experimental Cancer Research (ISREC) (M.L.S., C.B., M.A.S., M.D.P., M.L.I.-A.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Switzerland; and Institute for Molecular Engineering and Ben May Department of Cancer Research, University of Chicago, IL (W.W.K., M.A.S.). 2. From the Department of Human Genetics (H.H.), Department of Molecular, Cell and Developmental Biology (J.J.M., C.M.W., R.D.F., A.I.M., S.Z., M.L.I.-A.), Molecular Biology Institute (M.L.I.-A.), and Jonsson Comprehensive Cancer Center (M.L.I.-A.), University of California, Los Angeles; Institute for Bioengineering (IBI) (E.G., M.A.S.) and The Swiss Institute for Experimental Cancer Research (ISREC) (M.L.S., C.B., M.A.S., M.D.P., M.L.I.-A.), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Switzerland; and Institute for Molecular Engineering and Ben May Department of Cancer Research, University of Chicago, IL (W.W.K., M.A.S.). arispe@mcdb.ucla.edu.
Abstract
OBJECTIVE: Perivascular cells, including pericytes, macrophages, smooth muscle cells, and other specialized cell types, like podocytes, participate in various aspects of vascular function. However, aside from the well-established roles of smooth muscle cells and pericytes, the contributions of other vascular-associated cells are poorly understood. Our goal was to ascertain the function of perivascular macrophages in adult tissues under nonpathological conditions. APPROACH AND RESULTS: We combined confocal microscopy, in vivo cell depletion, and in vitro assays to investigate the contribution of perivascular macrophages to vascular function. We found that resident perivascular macrophages are associated with capillaries at a frequency similar to that of pericytes. Macrophage depletion using either clodronate liposomes or antibodies unexpectedly resulted in hyperpermeability. This effect could be rescued when M2-like macrophages, but not M1-like macrophages or dendritic cells, were reconstituted in vivo, suggesting subtype-specific roles for macrophages in the regulation of vascular permeability. Furthermore, we found that permeability-promoting agents elicit motility and eventual dissociation of macrophages from the vasculature. Finally, in vitro assays showed that M2-like macrophages attenuate the phosphorylation of VE-cadherin upon exposure to permeability-promoting agents. CONCLUSIONS: This study points to a direct contribution of macrophages to vessel barrier integrity and provides evidence that heterotypic cell interactions with the endothelium, in addition to those of pericytes, control vascular permeability.
OBJECTIVE: Perivascular cells, including pericytes, macrophages, smooth muscle cells, and other specialized cell types, like podocytes, participate in various aspects of vascular function. However, aside from the well-established roles of smooth muscle cells and pericytes, the contributions of other vascular-associated cells are poorly understood. Our goal was to ascertain the function of perivascular macrophages in adult tissues under nonpathological conditions. APPROACH AND RESULTS: We combined confocal microscopy, in vivo cell depletion, and in vitro assays to investigate the contribution of perivascular macrophages to vascular function. We found that resident perivascular macrophages are associated with capillaries at a frequency similar to that of pericytes. Macrophage depletion using either clodronate liposomes or antibodies unexpectedly resulted in hyperpermeability. This effect could be rescued when M2-like macrophages, but not M1-like macrophages or dendritic cells, were reconstituted in vivo, suggesting subtype-specific roles for macrophages in the regulation of vascular permeability. Furthermore, we found that permeability-promoting agents elicit motility and eventual dissociation of macrophages from the vasculature. Finally, in vitro assays showed that M2-like macrophages attenuate the phosphorylation of VE-cadherin upon exposure to permeability-promoting agents. CONCLUSIONS: This study points to a direct contribution of macrophages to vessel barrier integrity and provides evidence that heterotypic cell interactions with the endothelium, in addition to those of pericytes, control vascular permeability.
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