The migration of leukocytes through the endothelium to sites of infection or inflammation is a key process for the maintenance of physiological defense mechanisms. When this process is dis-regulated and becomes chronic, inflammatory diseases such as arteriosclerosis and arthritis manifest. The steps in leukocyte transmigration (TM) 5 are initiated though activation of the endothelial cells (ECs) by cytokines such as TNF-␣, interleukin-1, and interleukin-6. The selectins initiate the rolling and tethering of leukocytes to the endothelium. This step permits the engagement between ␤ 2 and ␤ 1 integrins with intercellular cell adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) to allow firm adhesion and spreading of leukocytes. ECs express low levels of ICAM-1 and VCAM-1, but cytokine stimulation elevates the expression of these receptors on ECs. The migration of leukocytes through the EC barrier involves platelet endothelial cell adhesion molecule-1 and junctional adhesion molecules. Finally, proteolytic degradation of the basement membrane extracellular matrix by metalloproteinases (MPs) in particular is required to promote extravasation (reviewed in Refs. 1 and 2).Although ICAM-1, VCAM-1, and platelet endothelial cell adhesion molecule-1 play an important role in in vivo and in vitro experimental models of TM (1-4), there is little data on the mechanistic role of the individual adhesion molecules. ICAM-1 comprises of five immunoglobulin-like motifs on the extracellular surface, followed by a stem, a transmembrane domain, and a short cytoplasmic tail (5). The cytoplasmic tail contains three tyrosine residues, two of which become phosphorylated at positions 485 and 474 upon ligation to modulate ICAM-1 function (6, 7). The role of these residues in leukocyteendothelial migration has not yet been defined.Proteolysis is an important step during and after transmigration (8, 9), as degradation of the basement membrane and matrix of the media (of larger vessels) or stroma is required. The zinc-dependent MPs belonging to the metzincin family possess a highly conserved catalytic domain, yet have an enormous * This work was supported in part by National Institutes of Health Grant PO1ES011860, the Jewish Hospital Foundation, Louisville (to S. E. D.), and an American Heart Association Postdoctoral Award (to S. D. S.) from the Ohio Valley Affiliate. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in the U.S. The vision-threatening processes of neuroglial and vascular dysfunction in DR occur in concert, driven by hyperglycemia and propelled by a pathway of inflammation, ischemia, vasodegeneration, and breakdown of the blood retinal barrier. Currently, no therapies exist for normalizing the vasculature in DR. Here, we show that a single intravitreal dose of adeno-associated virus serotype 2 encoding a more stable, soluble, and potent form of angiopoietin 1 (AAV2.COMP-Ang1) can ameliorate the structural and functional hallmarks of DR in Ins2Akita mice, with sustained effects observed through six months. In early DR, AAV2.COMP-Ang1 restored leukocyte-endothelial interaction, retinal oxygenation, vascular density, vascular marker expression, vessel permeability, retinal thickness, inner retinal cellularity, and retinal neurophysiological response to levels comparable with nondiabetic controls. In late DR, AAV2.COMP-Ang1 enhanced the therapeutic benefit of intravitreally delivered endothelial colony-forming cells by promoting their integration into the vasculature and thereby stemming further visual decline. AAV2.COMP-Ang1 single-dose gene therapy can prevent neurovascular pathology, support vascular regeneration, and stabilize vision in DR.

Kanekar, Shami, Olena V. Bogdanova, Paul R. Olson, Young-Hoon Sung, Kristen E. D'Anci, and Perry F. Renshaw. Hypobaric hypoxia induces depression-like behavior in female Sprague-Dawley rats, but not males. High Alt Med Biol 16:52-60, 2015-Rates of depression and suicide are higher in people living at altitude, and in those with chronic hypoxic disorders like asthma, chronic obstructive pulmonary disorder (COPD), and smoking. Living at altitude exposes people to hypobaric hypoxia, which can lower rat brain serotonin levels, and impair brain bioenergetics in both humans and rats. We therefore examined the effect of hypobaric hypoxia on depression-like behavior in rats. After a week of housing at simulated altitudes of 20,000 ft, 10,000 ft, or sea level, or at local conditions of 4500 ft (Salt Lake City, UT), Sprague Dawley rats were tested for depression-like behavior in the forced swim test (FST). Time spent swimming, climbing, or immobile, and latency to immobility were measured. Female rats housed at altitude display more depression-like behavior in the FST, with significantly more immobility, less swimming, and lower latency to immobility than those at sea level. In contrast, males in all four altitude groups were similar in their FST behavior. Locomotor behavior in the open field test did not change with altitude, thus validating immobility in the FST as depression-like behavior. Hypobaric hypoxia exposure therefore induces depression-like behavior in female rats, but not in males.

No abstract