These results were veried by wholemount in situ hybridization. It is conceivable that the apoptosis found in the mesenchymal cells accounts for this defect.Further examination showed that the dilated embryonic blood vessels were surrounded by reduced smooth muscle cells.The embryos also showed apoptosis of the mesenchyme, often leading to a nearly complete loss of this cell type in the most severely affected individuals.These observations suggest that SMAD plays an essential role during vascular Citric acid Development.Histological sections through the embryos in A and B showing abnormal blood vessels in the limb bud.Histological analysis revealed that the layer of endothelial cells was dissociated from mesenchymal cells in mutant embryos, suggesting that the interaction between the endothelial and mesenchymal cells may be affected.Siblings exhibit little staining in the head in the head TUNEL staining of histological sections.These embryos exhibited extremely enlarged and abnormal blood vessels, which lled the embryonic interior.We feel that the severity of the angiogenesis defect in these very severely affected embryos was a secondary consequence of the mesenchymal apoptosis.If the mesenchymal cells were absent they could not communicate any angiogenic signals to the endothelium, differentiate into vascular support cells, or physically support the blood vessels.The apoptosis was most concentrated in the mesenchyme of the head and somites. In addition, a number of murine mutants have been examined that lack normal vasculature in the yolk sac or embryo, but do not exhibit a similar pattern of mesenchymal cell death seen here, including t, angiopoietin and others.In our preliminary results we have found highdegree chimeras with wildtype yolk sacs that nevertheless contain highly abnormal embryos. These discrepancy can be explained in multiple ways.Because mutant yolk sacs are poorly vascularized, there is a possibility that the increased progenitors seen in the in vitro hematopoiesis progenitor assay resulted from the trapping of these cells in the yolk sac.This is unlikely, since the increase in progenitors is only limited to the myeloid lineage.However, the mutant yolk sacs yielded an increased number of myeloid progenitors.Development. Development. , is hemizygously lost and not mutated in the retained allele in human leukemia cell line HL.Cell. Accumulating evidence suggests that signal transducer and activator of transcription, mainly STAT, play an important role in angiogenesis under both physiological and pathological conditions in addition to cell survival, proliferation, differentiation, and oncogenesis.STAT, as a critical multifunctional mediator, regulates many aspects of angiogenesis at the transcriptional level.It is noteworthy that angiogenesis has been implicated in considerable disorders so far, and either excessive or insufcient angiogenesis contributes to the pathogenesis of angiogenesisdependent diseases such as rheumatoid arthritis, cancer, and cardiovascular disease.Therefore, it is not surprising that constitutive activation of STAT Heptaminol hydrochloride signaling has been observed in an increasing number of human cancers.In addition, STAT is able to regulate the innate and adaptive immune responses during cancer development.Recently, the constitutively activated STAT has been reported to upregulate VEGF expression and thereby induce tumor angiogenesis, demonstrating that constitutive STAT signaling contributes to tumorigenesis through multiple mechanisms.Accumulating evidence is dening a pivotal role for constitutively activated STAT in tumor angiogenesis.