Assessing Therapeutic Angiogenesis in a Murine Model of Hindlimb Ischemia.

Critical limb ischemia (CLI) is a serious condition that entails a high risk of lower limb amputation. Despite revascularization being the gold-standard therapy, a considerable number of CLI patients are not suited for either surgical or endovascular revascularization. Angiogenic therapies are emerging as an option for these patients but are currently still under investigation.

Low-dose ionizing radiation induces therapeutic neovascularization in a pre-clinical model of hindlimb ischemia.

Aims: We have previously shown that low-dose ionizing radiation (LDIR) induces angiogenesis but there is no evidence that it induces neovascularization in the setting of peripheral arterial disease. Here, we investigated the use of LDIR as an innovative and non-invasive strategy to stimulate therapeutic neovascularization using a model of experimentally induced hindlimb ischemia (HLI).

Methods And Results: After surgical induction of unilateral HLI, both hindlimbs of female C57BL/6 mice were sham-irradiated or irradiated with four daily fractions of 0.

Transthyretin proteins regulate angiogenesis by conferring different molecular identities to endothelial cells.

Familial amyloidotic polyneuropathy (FAP) has a high prevalence in Portugal, and the most common form of hereditary amyloidosis is caused by an amyloidogenic variant of transthyretin (TTR) with a substitution of methionine for valine at position 30 (V30M). Until now, the available efficient therapy is liver transplantation, when performed in an early phase of the onset of the disease symptoms. However, transplanted FAP patients have a significantly higher incidence of early hepatic artery thrombosis compared with non-FAP transplanted patients.

CD6 attenuates early and late signaling events, setting thresholds for T-cell activation.

The T lineage glycoprotein CD6 is generally considered to be a costimulator of T-cell activation. Here, we demonstrate that CD6 significantly reduces early and late T-cell responses upon superantigen stimulation or TCR triggering by Abs. Measuring calcium mobilization in single cells responding to superantigen, we found that human T cells expressing rat CD6 react significantly less well compared with T cells not expressing the exogenous receptor.

Low doses of ionizing radiation promote tumor growth and metastasis by enhancing angiogenesis.

Radiotherapy is a widely used treatment option in cancer. However, recent evidence suggests that doses of ionizing radiation (IR) delivered inside the tumor target volume, during fractionated radiotherapy, can promote tumor invasion and metastasis. Furthermore, the tissues that surround the tumor area are also exposed to low doses of IR that are lower than those delivered inside the tumor mass, because external radiotherapy is delivered to the tumor through multiple radiation beams, in order to prevent damage of organs at risk.

Protein interactions between CD2 and Lck are required for the lipid raft distribution of CD2.

In T lymphocytes, lipid rafts are preferred sites for signal transduction initiation and amplification. Many cell membrane receptors, such as the TCR, coreceptors, and accessory molecules associate within these microdomains upon cell activation. However, it is still unclear in most cases whether these receptors interact with rafts through lipid-based amino acid modifications or whether raft insertion is driven by protein-protein interactions.

Extracellular isoforms of CD6 generated by alternative splicing regulate targeting of CD6 to the immunological synapse.

The great majority of mammalian genes yield multiple transcripts arising from differential mRNA processing, but in very few instances have alternative forms been assigned distinct functional properties. We have cloned and characterized a new isoform of the accessory molecule CD6 that lacks the CD166 binding domain and is expressed in rat and human primary cells. The novel isoform, CD6Deltad3, results from exon 5 skipping and consequently lacks the third scavenger receptor cysteine-rich (SRCR) domain of CD6.

OX52 is the rat homologue of CD6: evidence for an effector function in the regulation of CD5 phosphorylation.

The MRC OX52 monoclonal antibody is a marker of rat T lymphocytes. We have cloned by polymerase chain reaction the rat homologue of CD6, and fluorescein-activated cell sorter analysis and immunoprecipitations using OX52 in COS7 cells transfected with rat CD6 cDNA showed that CD6 is the cell-surface molecule recognized by OX52. Immunoprecipitation analysis showed that CD6 coprecipitated with CD5, which in turn, was coprecipitated equivalently with CD2, CD6, and the T cell receptor (TCR), but the fraction of CD5 associated with CD6 was highly phosphorylated in kinase assays, in marked contrast with the low level of phosphorylation of CD5 associated with TCR or CD2.

CD2 physically associates with CD5 in rat T lymphocytes with the involvement of both extracellular and intracellular domains.

T lymphocytes can be activated and induced to proliferate through stimulation of the CD2 glycoprotein with functional combinations of CD2 antibodies. However, this mechanism of signal transduction via CD2 is still not fully understood. We have investigated which molecules on the T cell surface preferentially associate in Cis with CD2 and may regulate its signaling properties.