"The later stage of pancreas development includes paracrine VEGF-A signaling, which allows the formation of a branching capillary network in islets and interaction of islets with the circulatory system . Lack of or excess blood vessels in islets do not substantially impair later-stage endocrine pancreas development but do have moderate effects on further development of endocrine cells . These findings suggest that disruption of STAT3 and VEGF-A signaling pathways in the pancreas, along with microvascular alterations, may affect islet formation and, thus, insulin secretory function in vivo. "
[Show abstract][Hide abstract] ABSTRACT: Our previous studies have shown that signal transducer and activator of transcription 3 (STAT3) signaling is important for the development of pancreatic microvasculature via its regulation of vascular endothelial growth factor-A (VEGF-A). Pancreas-specific STAT3-KO mice exhibit glucose intolerance and impaired insulin secretion in vivo, along with microvascular alterations in the pancreas. However, the specific role of STAT3 signaling in the regulation of pancreatic islet development and function is not entirely understood.
To investigate the role of STAT3 signaling in the formation and maintenance of pancreatic islets, we studied pancreas-specific STAT3-KO mice. Histological analysis showed that STAT3 deficiency affected pancreatic islet morphology. We found an increased proportion of small-sized islets and a reduced fraction of medium-sized islets, indicating abnormal islet development in STAT3-KO mice. Interestingly, the islet area relative to the whole pancreas area in transgenic and control mice was not significantly different. Immunohistochemical analysis on pancreatic cryosections revealed abnormalities in islet architecture in STAT3-KO mice: the pattern of peripheral distribution of glucagon-positive α-cells was altered. At the same time, islets belonging to different size categories isolated from STAT3-KO mice exhibited normal glucose-stimulated insulin secretion in perifusion experiments in vitro when compared to control mice.
Our data demonstrate that STAT3 signaling in the pancreas is required for normal islet formation and/or maintenance. Altered islet size distribution in the KO mice does not result in an impaired islet secretory function in vitro. Therefore, our current study supports that the glucose intolerance and in vivo insulin secretion defect in pancreas-specific STAT3-KO mice is due to altered microvasculature in the pancreas, and not intrinsic beta-cell function.
PLoS ONE 07/2013; 8(7):e71277. DOI:10.1371/journal.pone.0071277 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In multicellular organisms, vascular tissue is necessary to establish a circulation that delivers nutrients and oxygen, removes waste products, and provides a means for interorgan communication (Risau, 1997). In animals, the vasculature is comprised of blood vessels, which permeate most tissues to ensure sufficient oxygen diffusion. Blood vessels are lined by a specialized cell type called endothelial cells, and, given their ubiquitous presence, it is not surprising that they have evolved functions beyond nutrient and oxygen transport. In recent years, significant progress has been made in describing the reciprocal relationship between the endothelial compartment and its surrounding microenvironment. It is now apparent that endothelial cells provide inductive signals during organ development as well as cell guidance molecules involved in patterning. Conversely, the vasculature responds to cues from the parenchyma that bestow upon it tissue-specific functions. Similar signals function under pathological conditions, where endothelial cells play a critical role in defining the local immune response and provide support for tumor growth. Given their vital importance to tissue survival, many of these mechanisms are being targeted in hopes of limiting tumor growth and ameliorating destructive inflammatory diseases. In this review, we discuss the major advances leading to the current understanding of how endothelial cell interactions may influence development and the adult state. We first focus on relevant advances in vasculogenesis/angiogenesis and the reciprocal signals that function during this process. Then, the mechanisms by which endothelial cells influence organogenesis are highlighted with a final discussion on their relation to pathophysiology, particularly tumorigenesis.
[Show abstract][Hide abstract] ABSTRACT: Myc-deficient mice fail to develop normal vascular networks and Myc-deficient embryonic stem cells fail to provoke a tumor angiogenic response when injected into immune compromised mice. However, the molecular underpinnings of these defects are poorly understood. To assess whether Myc indeed contributes to embryonic vasculogenesis we evaluated Myc function in Xenopus laevis embryogenesis. Here, we report that Xc-Myc is required for the normal assembly of endothelial cells into patent vessels during both angiogenesis and lymphangiogenesis. Accordingly, the specific knockdown of Xc-Myc provokes massive embryonic edema and hemorrhage. Conversely, Xc-Myc overexpression triggers the formation of ectopic vascular beds in embryos. Myc is required for normal expression of Slug/Snail2 and Twist, and either XSlug/Snail2 or XTwist could compensate for defects manifest by Xc-Myc knockdown. Importantly, knockdown of Xc-Myc, XSlug/Snail2 or XTwist within the lateral plate mesoderm, but not the neural crest, provoked embryonic edema and hemorrhage. Collectively, these findings support a model in which Myc, Twist and Slug/Snail2 function in a regulatory circuit within lateral plate mesoderm that directs normal vessel formation in both the vascular and lymphatic systems.
Development 07/2008; 135(11):1903-11. DOI:10.1242/dev.011296 · 6.46 Impact Factor
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