Rationale: Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications.Conclusions: The NEDD9-P-selectin protein-protein interaction is a modifiable target with which to inhibit platelet-pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.

Sheets AR, Fülöp P, Derdák Z, Kassai A, Sabo E, Mark NM, Paragh G, Wands JR, Baffy G. Uncoupling protein-2 modulates the lipid metabolic response to fasting in mice. Am J Physiol Gastrointest Liver Physiol 294: G1017-G1024, 2008. First published February 21, 2008 doi:10.1152/ajpgi.00016.2008.-Uncoupling protein-2 (UCP2) regulates insulin secretion by controlling ATP levels in ␤-cells. Although UCP2 deficiency improves glycemic control in mice, increased expression of UCP2 interferes with glucose-stimulated insulin secretion. These observations link UCP2 to ␤-cell dysfunction in type 2 diabetes with a perplexing evolutionary role. We found higher residual serum insulin levels and blunted lipid metabolic responses in fasted ucp2 Ϫ/Ϫ mice, supporting the concept that UCP2 evolved to suppress insulin effects and to accommodate the fuel switch to fatty acids during starvation. In the absence of UCP2, fasting initially promotes peripheral lipolysis and hepatic fat accumulation at less than expected rates but culminates in protracted steatosis, indicating diminished hepatic utilization and clearance of fatty acids. We conclude that UCP2-mediated control of insulin secretion is a physiologically relevant mechanism of the metabolic response to fasting. prolonged fasting; lipolysis; steatosis; insulin secretion UNCOUPLING PROTEIN (UCP) 2, a member of the anion carrier protein superfamily, is a widely distributed constituent of the mitochondrial inner membrane (6, 35). Although UCP2 was identified over 10 years ago by molecular cloning, its biological role and evolutionary aspects remain debated (6,29,35,40). Based on its significant homology with the brown adipose tissue-specific UCP1 (thermogenin), UCP2 was predicted to regulate energy balance. Subsequent observations did not confirm this prediction, and UCP2 appears to have a complex function yet to be fully explored (6,29,35,40). Similar to other uncoupling proteins, UCP2 lowers the mitochondrial membrane potential by mediating proton leak across the inner membrane (6). As a result, UCP2 has the ability to interfere with the function of F 1 F 0 ATP synthase and to alter the matrix ATP-to-ADP ratio (6).Soon after its discovery, the importance of UCP2 was recognized in pancreatic ␤-cells, where UCP2 acts as a negative regulator of glucose-stimulated insulin secretion (GSIS) (30, 51). Pancreatic ␤-cells sense blood glucose through its metabolism that results in increased levels of intracellular ATP and triggers GSIS to maintain glucose homeostasis (41). Because of more efficient oxidative phosphorylation and increased rates of mitochondrial ATP synthesis, UCP2 deficiency is associated with enhanced ␤-cell insulin secretory capacity in ucp2 Ϫ/Ϫ mice and allows the partial correction of diabetes in leptin-deficient ob/ob mice (51). In contrast, overexpression of UCP2 in ␤-cells reduces intracellular ATP levels, leading to diminished GSIS (21). Because increased UCP2 expression of ␤-cells is associated with obesity, UCP2 has been linked to impaired insulin production in typ...

Debridement, the removal of diseased, nonviable tissue, is critical for clinicians to readily assess wound status and prepare the wound bed for advanced therapeutics or downstream active healing. Removing necrotic slough and eschar through surgical or mechanical methods is less specific and may be painful for patients. Enzymatic debridement agents, such as Clostridial collagenase, selectively and painlessly degrade devitalized tissue. In addition to its debriding activities, highly-purified Clostridial collagenase actively promotes healing, and our past studies reveal that extracellular matrices digested with this enzyme yield peptides that activate cellular migratory, proliferative and angiogenic responses to injury in vitro, and promote wound closure in vivo. Intriguingly, while collagenase Santyl® ointment, a sterile preparation containing Clostridial collagenases and other non-specific proteases, is a well-accepted enzymatic debridement agent, its role as an active healing entity has never been established. Based on our previous studies of pure Clostridial collagenase, we now ask whether the mixture of enzymes contained within Santyl® produces matrix-derived peptides that promote cellular injury responses in vitro and stimulate wound closure in vivo. Here, we identify novel collagen fragments, along with collagen-associated peptides derived from thrombospondin-1, multimerin-1, fibronectin, TGFβ-induced protein ig-h3 and tenascin-C, generated from Santyl® collagenase-digested human dermal capillary endothelial and fibroblastic matrices, which increase cell proliferation and angiogenic remodeling in vitro by 50–100% over controls. Using an established model of impaired healing, we further demonstrate a specific dose of collagenase from Santyl® ointment, as well as the newly-identified and chemically-synthesized ECM-derived peptides significantly increase wound re-epithelialization by 60–100% over saline-treated controls. These results not only confirm and extend our earlier studies using purified collagenase- and matrix-derived peptides to stimulate healing in vitro and in vivo, but these Santyl®-generated, matrix-derived peptides may also represent exciting new opportunities for creating advanced wound healing therapies that are enabled by enzymatic debridement and potentially go beyond debridement.

Effects from the diabetic microenvironment appear sustainable in cell culture: pericytes derived from diabetic donor eyes seemingly possess a "metabolic memory" in vitro, which may be linked to original donor health status. Diabetes- and pericyte-dependent effects on EC growth and angiogenesis may reflect alterations in bioactive lipid, angiocrine, and chemomechanical signaling. Altogether, our results suggest that diabetes alters pericyte contractile phenotype and cytoskeletal signaling, which ultimately may serve as a key, initiating event required for retinal endothelial reproliferation, angiogenic activation, and the pathological neovascularization accompanying proliferative diabetic retinopathy.