The Tie2-agonist Vasculotide rescues mice from influenza virus infection.

Seasonal influenza virus infections cause hundreds of thousands of deaths annually while viral mutation raises the threat of a novel pandemic strain. Antiviral drugs exhibit limited efficacy unless administered early and may induce viral resistance. Thus, targeting the host response directly has been proposed as a novel therapeutic strategy with the added potential benefit of not eliciting viral resistance.

Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality.

A synthetic 7-mer, HHHRHSF, was recently identified by screening a phage display library for binding to the Tie-2 receptor. A polyethylene-oxide clustered version of this peptide, termed vasculotide (VT), was reported to activate Tie-2 and promote angiogenesis in a mouse model of diabetic ulcer. We hypothesized that VT administration would defend endothelial barrier function against sepsis-associated mediators of permeability, prevent lung vascular leakage arising in endotoxemia, and improve mortality in endotoxemic mice.

Experimental assessment of pro-lymphangiogenic growth factors in the treatment of post-surgical lymphedema following lymphadenectomy.

Introduction: Lymphedema is a frequent consequence of lymph node excision during breast cancer surgery. Current treatment options are limited mainly to external compression therapies to limit edema development. We investigated previously, post-surgical lymphedema in a sheep model following the removal of a single lymph node and determined that autologous lymph node transplantation has the potential to reduce or prevent edema development.

Experimental assessment of autologous lymph node transplantation as treatment of postsurgical lymphedema.

Background: The authors' objective was to test whether the transplantation of an autologous lymph node into a nodal excision site in sheep would restore lymphatic transport function and reduce the magnitude of postsurgical lymphedema.

Methods: As a measure of lymph transport, iodine-125 human serum albumin was injected into prenodal vessels at 8 and 12 weeks after surgery, and plasma levels of the protein were used to calculate the transport rate of the tracer to blood (percent injected per hour). Edema was quantified from the circumferential measurement of the hind limbs.

Lymphedema development and lymphatic function following lymph node excision in sheep.

Background: Our objective was to develop an animal model of postsurgical lymphedema that would permit quantitation of edema and lymphatic function after the removal of a single popliteal lymph node in sheep.

Methods: As a measure of lymph transport, (125)I-human serum albumin was injected into prenodal vessels at 8, 12 and 16 weeks after nodal excision, and plasma levels of the protein tracer were used to calculate the transport rate of the tracer to blood (percent injected per hour). Edema was quantified from the circumferential measurement of the hind limbs.

Acceleration of diabetic wound healing by an angiopoietin peptide mimetic.

Angiopathies are one of the leading underlying causes of morbidity in diabetic patients. Poorly managed blood glucose levels contribute to vascular defects that manifest themselves in numerous different clinical conditions, including diabetic retinopathy, nephropathy, peripheral artery disease, and compromised wound healing. The angiopoietin family (Angs 1-4) has been shown to play a critical role in the growth and maintenance of vasculature.

The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis.

Nutrients and bioenergetics are prerequisites for proliferation and survival of mammalian cells. We present evidence that the cyclin-dependent kinase inhibitor p27(Kip1), is phosphorylated at Thr 198 downstream of the Peutz-Jeghers syndrome protein-AMP-activated protein kinase (LKB1-AMPK) energy-sensing pathway, thereby increasing p27 stability and directly linking sensing of nutrient concentration and bioenergetics to cell-cycle progression. Ectopic expression of wild-type and phosphomimetic Thr 198 to Asp 198 (T198D), but not unstable Thr 198 to Ala 198 (p27(T198A)) is sufficient to induce autophagy.

Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice.

Hemangioma of infancy is the most common neoplasm of childhood. While hemangiomas are classic examples of angiogenesis, the angiogenic factors responsible for hemangiomas are not fully understood. Previously, we demonstrated that malignant endothelial tumors arise in the setting of autocrine loops involving vascular endothelial growth factor (VEGF) and its major mitogenic receptor vascular endothelial growth factor receptor 2.

The roles of versican V1 and V2 isoforms in cell proliferation and apoptosis.

Versican is a large chondroitin sulfate proteoglycan belonging to the lectican family. Alternative splicing of versican generates at least four isoforms named V0, V1, V2, and V3. We have shown that the versican V1 isoform not only enhanced cell proliferation, but also modulated cell cycle progression and protected the cells from apoptosis.