ABSTRACT
Renal function declines with age and this is more pronounced in males than females. VEGF-A is essential for glomerular development and function but its role in other aspects of renal function is poorly understood. We therefore investigated the role of VEGF-A, derived specifically from haematopoietic and endothelial lineages in the kidney. We crossed VavCre and floxed Vegf-a mice allowing specific ablation of a single Vegf-a allele in the haematopoietic and endothelial lineages. Mutants were viable and fertile and had normal haematological composition, indicating that 50% gene dosage of Vegf-a in the Vav-expressing lineage is sufficient for establishing a functional haematopoietic system and mature vascular network. However, several abnormalities were observed in the kidney of the adult mutants. These included the formation of inclusion bodies in the proximal tubular cells, tubular atrophy and interstitial fibrosis. These features were observed in 9-11 month-old mutant animals. Most of these abnormalities have been described in aging kidneys in man, and were also observed in the older control mice (24 months). The pathological features appeared in mutant male animals at a younger age than in female mutants. This indicates that reduction in Vegf-a gene dosage in haematopoietic and endothelial lineages accelerates renal aging, suggesting that VEGF-A derived from these lineages may play a role in protecting the kidney from age-associated damage.
Subject(s)
Aging/metabolism , Cell Lineage , Endothelial Cells/metabolism , Hematopoietic Stem Cells/metabolism , Kidney/metabolism , Vascular Endothelial Growth Factor A/deficiency , Age Factors , Aging/genetics , Aging/pathology , Animals , Atrophy , Biomarkers/blood , Biomarkers/urine , Female , Fibrosis , Genotype , Inclusion Bodies/pathology , Kidney/pathology , Male , Mice , Mice, Knockout , Phenotype , Sex Factors , Vascular Endothelial Growth Factor A/geneticsABSTRACT
The endometrium is a dynamic tissue that undergoes periodic growth, remodeling and breakdown under the influence of ovarian steroid hormones. To investigate the molecular mechanisms underlying these processes, we used a murine model to mimic the decidualization and regression observed in humans. Ovariectomized mice were treated sequentially with steroid hormones, and subsequently, to induce decidualization, oil was injected into the uterine lumen. The animals were then divided into progesterone-maintained and progesterone-withdrawal groups. In the latter group, a process similar to menstruation was induced. The uterine tissues were collected at several time-points after the induction of decidualization. Histological analysis demonstrated that decidualization and tissue degeneration were successfully induced with similar features to those observed during the human menstrual cycle. Immunohistochemical, morphometric, and microarray-based techniques were used to study the cellular and molecular changes. The volume fractions of leukocytes, macrophages, and neutrophils, but not endothelial cells, increased in decidualized uteri and decreased after major tissue degradation was completed. The microarray data show that the levels of many transcripts that encode immune-related factors changed during the time-course used for this model, and the transcript levels of many of these factors paralleled the changes observed in the volume fractions of the immune cells. The results of the present study suggest that this model is a useful alternative to the use of non-human primates. Our findings also show that immune cells are recruited into the menstruating endometrium, and that immune-related genes are regulated in the uterus throughout menstruation.
