Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions.

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.

Results of a living donor kidney promotion program.

BACKGROUND: Living kidney donor transplantation, a treatment option for end-stage kidney failure, may achieve better results than cadaveric donor transplantation. Although its significant use in some countries is due to the scarcity of cadaveric donors, it is also useful because it reduces waiting time for young recipients and avoids dialysis when performed before starting renal replacement therapy. Due to the high rate of cadaveric donation in Spain, there has only been a limited increase in the number of living donor kidney transplantations. METHODS: In February 2004, we initiated a program to promote living kidney donation (LKD) through an information plan that was transmitted to the patients by dialysis nephrologists and chronic kidney failure outpatient clinics. RESULTS: From February 2004 to March 2010, we evaluated 109 donor and recipient pairs: parent to child (n=48 cases; 44%), spouses (n=32 cases; 29.3%), siblings (n=27; 24.7%), and uncle and nephew (n=2; 1.8%). The mean donor age (49±9 years) was significantly higher than the 39±13 years of the recipients (P<.01). In 45 cases (41.3%), the procedure led to of living kidney donor transplantation but in 58 (53.2%), a transplantation was not performed due to recipient problems (n=53) or donor problems (n=5). In 6 cases (5.5%), the evaluation is still pending. With the initiation of this project, it has been possible to significantly increase the rate of living kidney donor transplantation in our hospital from 0.8% (March to January 2004: 16/1964) to 4.2% (February 2004 to March 2010: 43/1022 transplants; P<.01). CONCLUSION: A policy of active information together with adequate studies of the potential donor and recipient significantly increased the number of living kidney donor transplantations. The profitability of the study procedure was 50%. The most frequent cause of noncompletion of the procedure was recipient-related problems.

Extended-release tacrolimus therapy in de novo kidney transplant recipients: single-center experience.

BACKGROUND: Available data for extended-release tacrolimus (Tac) except in clinical trials are limited. OBJECTIVE: To describe our initial experience with once-daily Tac in combination with corticosteroids and mycophenolate mofetil therapy in patients undergoing de novo renal transplantation. PATIENTS AND METHODS: In this retrospective, observational, single-center study, data were obtained for 49 adult recipients treated with extended-release Tac and 30 patients treated with standard-release Tac (control group). Mean (SD) follow-up in the 2 groups was 3.5 (2.5) months and 4.0 (2.6) months, respectively. The primary characteristics were comparable between the groups. RESULTS: The acute rejection rate in the extended-release group was 10%, and 13% in the standard-release group. Patient and graft survival rates were 98% and 96% vs 100% and 90%, respectively. Renal function in the 2 groups was comparable: serum creatinine concentration 1.3 (0.2) mg/dL vs 1.45 (0.4) mg/dL. At day 14 posttransplantation, Tac doses were 0.17 mg/kg/d vs 0.14 mg/kg/d, and blood concentrations were 9.0 ng/mL vs 14.0 ng/mL. In recipients older than 60 years, lower dosages of Tac resulted in blood concentrations similar to those in younger patients, with less variation in dosage. CONCLUSIONS: Short-term experience with extended-release Tac therapy in de novo renal recipients confirms its efficacy and safety. Adjusting blood concentrations in the immediate posttransplantation period is less difficult with extended-release Tac compared with the twice-daily formulation.

The placenta growth factor gene of the mouse.

Placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF) are angiogenic factors containing the 8-cysteine motif of platelet-derived growth factor (PDGF). Both PlGF and VEGF are mitogens for endothelial cells in vitro and promote neoangiogenesis in vivo. In addition, PlGF strongly potentiates the proliferative and the permeabilization effects exerted by VEGF on the vascular endothelium. We have now isolated the cDNA coding for mouse Plgf by screening a mouse heart cDNA library with the human PlGF sequence as probe. The human PlGF protein has two forms, PlGF-1 and PlGF-2, that arise from alternative splicing of a single gene mapping on Chromosome (Chr) 14; the isolated mouse Plgf cDNA encodes the longer of these two forms (PlGF-2). We show that the mouse Plgf-2 mRNA is the only transcript present in the normal tissues analyzed. Mouse Plgf-2 is a 158-amino-acid-long protein that shows 78% similarity (65% identity) to the human PlGF-2. Computer analysis reveals a putative signal peptide and three probable N-glycosylation sites, two of which are also conserved in human PlGF. The mouse Plgf gene was isolated and characterized; the gene is encoded by 7 exons spanning a 13-kb DNA interval. Finally, we have mapped the mouse Plgf gene to Chr 12, one cM from D12Mit5, and the human PlGF gene to 14q24, using both FISH and genetic crosses.