Physiological angiogenesis refers to a naturally occurring process of blood vessel growth and regression, and it occurs as an integral component of tissue repair and regeneration. During wound healing, sprouting and branching results in an extensive yet immature and leaky neovascular network that ultimately resolves by systematic pruning of extraneous vessels to yield a stable, well-perfused vascular network ideally suited to maintain tissue homeostasis. While the molecular mechanisms of blood vessel growth have been explored in numerous cell and animal models in remarkable detail, the endogenous factors that prevent further angiogenesis and control vessel regression have not received much attention and are largely unknown. In this review, we introduce the relevant literature from various disciplines to fill the gaps in the current limited understanding of the major molecular and biomechanical inducers of vascular regression. The processes are described in the context of endothelial cell biology during wound healing: hypoxia-driven activation and sprouting followed by apoptosis or maturation of cells comprising the vasculature. We discuss and integrate the likely roles of a variety of endogenous factors, including oxygen availability, vessel perfusion and shear stress, intracellular negative feedback mechanisms (Spry2, vasohibin), soluble cytokines (CXCL10), matrix-binding proteins (TSP, PEDF), protein cleavage products (angiostatin, vasostatin), matrix-derived anti-angiogenic peptides (endostatin, arresten, canstatin, tumstatin), and the biomechanical properties of remodeling the extra-cellular matrix itself. These factors aid in the spatio-temporal control of blood vessel pruning by inducing specific anti-angiogenic signaling pathways in activated endothelial cells, pathways which compete with pro-angiogenic and maturation signals in the resolving wound. Gaining more insight into these mechanisms is bound to shed light on unresolved questions regarding scar formation, tissue regeneration, and increase our understanding of the many diseases with angiogenic phenotypes, especially cancer.
Mouse mammary gland organ culture technique was utilized to determine the effects of retinoids on the prolactin-induced structural differentiation of the mammary gland. Thoracic glands from BALB/c mice pretreated with steroids differentiate in 6 days into alveolar structures in presence of insulin and prolactin. All-trans-retinoic acid and N-(-4-hydroxyphenyl)retinamide inhibit prolactin-induced structural changes in the glands. Retinyl acetate, which is effective against mammary carcinogenesis in the rat, but is ineffective against mouse mammary carcinogenesis, failed to inhibit such proliferation. These results were correlated with inhibition of [3H]thymidine incorporation into DNA in a dose related manner by retinoids effective in inhibiting mammary development.
High mol. wt genomic DNA was prepared from normal hamster pancreas and the solid and ascites variants of two different hamster transplantable carcinomas, one induced by N-nitrosobis(2-oxopropyl)amine and the other spontaneously occurring. This DNA was transfected into NIH/3T3 cells and resulted in cells that were capable of forming tumors when injected into nude mice. Analysis of the nude mouse tumors by Southern blotting revealed the presence of a band specific for hamster K-ras. Polymerase chain reaction (PCR)-mediated amplification of the K-ras codon 12-13 region of genomic DNA prepared from the transplantable tumors produced a 117 bp fragment which was analyzed by both allele-specific oligonucleotide hybridization and direct DNA sequencing. Oligonucleotide hybridization with probes specific for changes in the first or second position of codons 12 or 13 detected a G to A transversion in the second position of codon 12 in the chemically induced transplantable tumor, and a G to A change in the second position of codon 13 in the spontaneously occurring transplantable carcinomas. The result obtained for the chemically induced tumor was confirmed by direct dideoxy sequencing of the PCR-amplified product. These findings are the first to show a specific oncogene activation in an experimental pancreatic tumor model and also parallel the results recently reported for K-ras mutations in human pancreatic carcinoma.
Cellular retinoic acid-binding protein (CRABP) was detected in the nuclear fraction of N-methyl-N-nitrosourea-induced mammary cancers after the incubation of cytosol containing [3H]retinoic acid (RA)-bound CRABP with isolated nuclei. CRABP extracted from the nuclei in buffer containing 0.4 M-KCl sedimented as a 2 S component when subjected to sucrose-density-gradient analysis. [3H]RA-CRABP was found to be a prerequisite for the detection of nuclear binding, since the incubation of isolated nuclei or 0.4 M-KCl extract of the nuclei with [3H]RA did not result in any significant binding. Incubation of [3H]RA-CRABP at 25 or 30 degrees C before incubation with the nuclei neither altered the sedimentation coefficient nor enhanced the nuclear binding compared with 0 degrees C incubation. The tumour nuclei contained a saturable number of binding sites with a dissociation constant of 1.6 x 10(-9) M. These results indicate that the action of retinoic acid in the target organ may be mediated by its interaction with the nuclei.
SUMMARY: A modified procedure for culturing an entire thoracic pair of mammary glands from virgin mice is described. The glands are incubated in CMRL 1066 medium supplemented with hormones in a controlled atmosphere chamber with a gas phase of 50% 02, 5% CO~, and 45% N2 at 37 ° C.
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