Correlating Global Gene Regulation to Angiogenesis in the Developing Chick Extra-Embryonic Vascular System

Abstract

BackgroundFormation of blood vessels requires the concerted regulation of an unknown number of genes in a spatial-, time- and dosage-dependent manner. Determining genes, which drive vascular maturation is crucial for the identification of new therapeutic targets against pathological angiogenesis.Methology/Principal FindingsWe accessed global gene regulation throughout maturation of the chick chorio-allantoic membrane (CAM), a highly vascularized tissue, using pan genomic microarrays. Seven percent of analyzed genes showed a significant change in expression (>2-fold, FDR<5%) with a peak occurring from E7 to E10, when key morphogenetic and angiogenic genes such as BMP4, SMO, HOXA3, EPAS1 and FGFR2 were upregulated, reflecting the state of an activated endothelium. At later stages, a general decrease in gene expression occurs, including genes encoding mitotic factors or angiogenic mediators such as CYR61, EPAS1, MDK and MYC. We identified putative human orthologs for 77% of significantly regulated genes and determined endothelial cell enrichment for 20% of the orthologs in silico. Vascular expression of several genes including ENC1, FSTL1, JAM2, LDB2, LIMS1, PARVB, PDE3A, PRCP, PTRF and ST6GAL1 was demonstrated by in situ hybridization. Up to 9% of the CAM genes were also overexpressed in human organs with related functions, such as placenta and lung or the thyroid. 21–66% of CAM genes enriched in endothelial cells were deregulated in several human cancer types (P<.0001). Interfering with PARVB (encoding parvin, beta) function profoundly changed human endothelial cell shape, motility and tubulogenesis, suggesting an important role of this gene in the angiogenic process.Conclusions/SignificanceOur study underlines the complexity of gene regulation in a highly vascularized organ during development. We identified a restricted number of novel genes enriched in the endothelium of different species and tissues, which may play crucial roles in normal and pathological angiogenesis.

Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis

“…In normal animals, PRCP contributes to the production of bradykinin and angiotensin. [1][2][3][4][5][6][7] Both peptides bind to their constitutive receptors, the B2R and Mas, to contribute to the constitutive level of vascular NO that contributes to thrombosis protection ( Figure 7). Alternatively, PRCP gt/gt mice are hypertensive.…”

“…1,2 PRCP is up-regulated during the angiogenic processes of vascular development. 7 The exact physiologic role for PRCP is not completely known. A PRCP polymorphism (E112D) is linked to hypertension and preeclampsia.…”

“…10 PRCP is linked to metabolic syndrome in humans. 11 PRCP also degrades ␣-melanocyte stimulating hormone (␣-MSH [1][2][3][4][5][6][7][8][9][10][11][12][13] ) to its inactive ␣-MSH [1][2][3][4][5][6][7][8][9][10][11][12] form by cleaving its C-terminal Val. 12 ␣-MSH [1][2][3][4][5][6][7][8][9][10][11][12][13] stimulates an anorexigenic response.…”

Accessibilome of Human Glioblastoma: Collagen-VI-alpha-1 Is a New Target and a Marker of Poor Outcome

“…Therefore, we decided to additionally analyze a U87-based CAM model of human glioblastoma, previously shown to veritably depict the situation encountered in humans. 30 CAM tumors were subjected to the same analysis used for human samples. The analysis of six human glioblastomas and three U87 CAM-derived tumors led to the identification of 898 and 633 unique proteins, respectively.…”

Expression, characterization, and preliminary X-ray crystallographic analysis of recombinant murine Follistatin-like 1 expressed in Drosophila S2 cells

“…Involvement of FSTL1 in cardiovascular tissue regulation has been suggested (20,(27)(28)(29). Its expression in adult heart is induced in response to injurious conditions that promote myocardial hypertrophy and heart failure (21,30,31).…”