Growth regulation of the vascular system: an emerging role for adenosine

2005 ◽  
Vol 289 (2) ◽  
pp. R283-R296 ◽  
Author(s):  
Thomas H. Adair
Keyword(s):  
Growth Factors ◽  
Growth Regulation ◽  
Vascular System ◽  
Parenchymal Cell ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Hypoxic Conditions ◽  
And Migration ◽  
Parenchymal Cells ◽  
Control Hypothesis

The importance of metabolic factors in the regulation of angiogenesis is well understood. An increase in metabolic activity leads to a decrease in tissue oxygenation causing tissues to become hypoxic. The hypoxia initiates a variety of signals that stimulate angiogenesis, and the increase in vascularity that follows promotes oxygen delivery to the tissues. When the tissues receive adequate amounts of oxygen, the intermediate effectors return to normal levels, and angiogenesis ceases. An emerging concept is that adenosine released from hypoxic tissues has an important role in driving the angiogenesis. The following feedback control hypothesis is proposed: AMP is dephosphorylated by ecto-5′-nucleotidase, producing adenosine under hypoxic conditions in the extracellular space adjacent to a parenchymal cell (e.g., cardiomyocyte, skeletal muscle fiber, hepatocyte, etc.). Extracellular adenosine activates A2 receptors, which stimulates the release of vascular endothelial growth factor (VEGF) from the parenchymal cell. VEGF binds to its receptor (VEGF receptor 2) on endothelial cells, stimulating their proliferation and migration. Adenosine can also stimulate endothelial cell proliferation independently of VEGF, which probably involves modulation of other proangiogenic and antiangiogenic growth factors and perhaps an intracellular mechanism. In addition, hemodynamic factors associated with adenosine-induced vasodilation may have a role in the development and remodeling of the vasculature. Once a new capillary network has been established, and the diffusion/perfusion capabilities of the vasculature are sufficient to supply the parenchymal cells with adequate amounts of oxygen, adenosine and VEGF as well as other proangiogenic and antiangiogenic growth factors return to near-normal levels, thus closing the negative feedback loop. The available data indicate that adenosine might be an essential mediator for up to 50–70% of the hypoxia-induced angiogenesis in some situations; however, additional studies in intact animals will be required to fully understand the quantitative importance of adenosine.

Growth regulation of the vascular system: evidence for a metabolic hypothesis

1990 ◽  
Vol 259 (3) ◽  
pp. R393-R404 ◽  
Author(s):  
T. H. Adair ◽  
W. J. Gay ◽  
J. P. Montani
Keyword(s):  
Blood Flow ◽  
Blood Vessels ◽  
Growth Regulation ◽  
Vascular System ◽  
Major Influence ◽  
Control Element ◽  
Hypoxic Conditions ◽  
Control Growth ◽  
Vessel Growth ◽  
Tissue Cells

Prolonged imbalances between the perfusion capabilities of the blood vessels and the metabolic requirements of the tissue cells often lead to modification of the vasculature to satisfy the tissue needs. This homeostatic response appears to be bidirectional, since the vascularity of a tissue can increase or decrease in parallel with primary changes in metabolic rate. The factors that mediate the responses are not well understood, but oxygen has been implicated as a major control element, since vessel growth increases during hypoxic conditions and decreases during hyperoxic conditions. The following feedback control hypothesis may apply to many different physiological situations. Decreased oxygenation causes the tissues to become hypoxic, and this initiates a variety of signals that lead to the growth of blood vessels. The increase in vascularity promotes oxygen delivery to the tissue cells by decreasing diffusion distances, increasing capillary surface area, and increasing the maximum rate of blood flow. When the tissues receive adequate amounts of oxygen even during periods of peak activity, the intermediate effectors return to normal levels, and this negative signal, in turn, stops the further development of the vasculature. Although the effector mechanisms of the hypoxic stimulus are still being investigated, adenosine, which is produced in hypoxic tissues, appears to mediate hypoxia-induced increases in vascularity in some instances. Roles for fibroblast growth factor as well as mechanical factors associated with vasodilation and increased blood flow are postulated. Although blood vessel growth is a multifactorial process, a major influence in its regulation appears to be metabolic need. If this view is correct, it may be found that many of the quantitatively significant factors that control growth in a given vasculature are themselves modulated or controlled by metabolic signals reflecting the nutritional status of the tissues which that vasculature supplies.

Creation of retinal vein occlusion model in cynomolgusmonkeys and determination of its pathological features

2020 ◽  
Vol 17 ◽  
Author(s):  
Satoshi Inagaki ◽  
Masamitsu Shimazawa ◽  
Wataru Otsu ◽  
Tomoaki Araki ◽  
Yosuke Numata ◽  
...  
Keyword(s):  
Growth Factors ◽  
Retinal Vein Occlusion ◽  
Vascular System ◽  
Retinal Thickness ◽  
Chronic Phase ◽  
Vascular Leakage ◽  
Foveal Avascular Zone ◽  
Retinal Edema ◽  
Vein Occlusion ◽  
Angiopoietin 2

Objective: A retinal vein occlusion (RVO) is a relatively common retinal vascular disorder especially in the elder-ly. Many experiments have been performed on patients with a RVO but performing any type of experiments and especially longitudinal experiments on humans is difficult if not impossible on ethical grounds. Therefore, we have created a retinal vein occlusion (RVO) model by laser irradiation of cynomolgus monkeysafter an intravenous injection of rose bengal. Weevaluated the pathological changes of the retina, and the effects of ranibizumab, an anti-vascular endothelial growth factor (VEGF) antibody, on the characteristics of the RVO. Methods: The integrity of the vascular system was evaluated by fluorescein angiography (FA), and the retinal thickness and volume were determined by optical coherence tomography (OCT). The cytokines and growth factors in the aqueous humor were identified by multiplex profiling. Results: Our results showed that ranibizumab decreased the degree of vascular leakage and retinal edema at 1-3 days (acute phase) and 3-7 days (subacute phase), and suppressed foveal thinning at 28-42 days (chronic phase) after the laser irradia-tion. Ranibizumab also decreased the area of the foveal avascular zone, and the area was negatively and significantly corre-lated with the thickness of the ganglion cell layer (GCL) complex. Furthermore, ranibizumab reduced the increased expres-sion of VEGF in the aqueous humour, but did not affect the expressions of interleukin-6 (IL-6), monocyte chemotactic pro-tein-1 (MCP-1), angiopoietin-1 (ANG-1), or angiopoietin-2 (ANG-2).Thesefindings suggest that ranibizumab attenuates the retinal edema and subsequent retinal atrophy in partby neutralizing VEGF. However, other cytokines and growth factors were also affected by the ranibizumab which suggests that not only VEGF but also other unidentified agents might play a role in the pathogenesis of the RVO. Conclusion: We have created a non-human primate RVO model, which resembles the clinical RVO pathology. In this model, an injection of ranibizumab leads to a reduction in the vascular leakage and the retinal thickness and volume by blockingthe expression of VEGF. Our model might be useful for investigating the pathological mechanisms of RVOs and explore new therapeutic agents for RVO.

scholarly journals Effects of bone morphogenetic proteins on epithelial repair

2021 ◽  
pp. 153537022110281
Author(s):  
Yu Hou ◽  
Yu-Xi He ◽  
Jia-Hao Zhang ◽  
Shu-Rong Wang ◽  
Yan Zhang
Keyword(s):  
Growth Factors ◽  
Epithelial Cells ◽  
Bone Morphogenetic Proteins ◽  
Epithelial Tissue ◽  
Epithelial Repair ◽  
Multiple Functions ◽  
Epithelial Damage ◽  
Damage Repair ◽  
And Migration ◽  
Proliferation And Migration

Epithelial tissue has important functions such as protection, secretion, and sensation. Epithelial damage is involved in various pathological processes. Bone morphogenetic proteins (BMPs) are a class of growth factors with multiple functions. They play important roles in epithelial cells, including in differentiation, proliferation, and migration during the repair of the epithelium. This article reviews the functions and mechanisms of the most profoundly studied BMPs in the process of epithelial damage repair and their clinical significance.

scholarly journals Crosstalk between MUC1 and VEGF in angiogenesis and metastasis: a review highlighting roles of the MUC1 with an emphasis on metastatic and angiogenic signaling

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Farnaz Khodabakhsh ◽  
Parnaz Merikhian ◽  
Mohammad Reza Eisavand ◽  
Leila Farahmand
Keyword(s):  
Tumor Growth ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Endothelial Cell Proliferation ◽  
Mucin 1 ◽  
Signaling Transduction ◽  
Growth And Survival ◽  
Angiogenic Proteins ◽  
Angiogenic Effect ◽  
And Migration

AbstractVEGF and its receptor family (VEGFR) members have unique signaling transduction system that play significant roles in most pathological processes, such as angiogenesis in tumor growth and metastasis. VEGF-VEGFR complex is a highly specific mitogen for endothelial cells and any de-regulation of the angiogenic balance implicates directly in endothelial cell proliferation and migration. Moreover, it has been shown that overexpressing Mucin 1 (MUC1) on the surface of many tumor cells resulting in upregulation of numerous signaling transduction cascades, such as growth and survival signaling pathways related to RTKs, loss of cell-cell and cell-matrix adhesion, and EMT. It promotes gene transcription of pro-angiogenic proteins such as HIF-1α during periods of oxygen scarcity (hypoxia) to enhance tumor growth and angiogenesis stimulation. In contrast, the cytoplasmic domain of MUC1 (MUC1-C) inhibits apoptosis, which in turn, impresses upon cell fate. Besides, it has been established that reduction in VEGF expression level correlated with silencing MUC1-C level indicating the anti-angiogenic effect of MUC1 downregulation. This review enumerates the role of MUC1-C oncoprotein and VEGF in angiogenesis and metastasis and describes several signaling pathways by which MUC1-C would mediate the pro-angiogenic activities of cancer cells.

scholarly journals miR-27b Suppresses Endothelial Cell Proliferation and Migration by Targeting Smad7 in Kawasaki Disease

2018 ◽  
Vol 48 (4) ◽  
pp. 1804-1814 ◽  
Author(s):  
Xing Rong ◽  
Donghui Ge ◽  
Danping Shen ◽  
Xianda Chen ◽  
Xuliang Wang ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Kawasaki Disease ◽  
Therapeutic Target ◽  
Umbilical Vein ◽  
Luciferase Reporter ◽  
Endothelial Cell Proliferation ◽  
Cell Functions ◽  
Potential Biomarker ◽  
And Migration ◽  
Proliferation And Migration

Background/Aims: Increasing evidence indicates that microRNAs (miRNAs) play important roles in Kawasaki disease (KD). Our previous study demonstrated that hsa-miR-27b-3p (miR-27b) was up-regulated in KD serum. However, the specific role of miR-27b in KD remains unclear. We aimed to investigate that miR-27b could be a biomarker and therapeutic target for KD treatment. As well, the specific mechanism of miR-27b effecting endothelial cell functions was studied. Methods: The expression of miR-27b and Smad7 was measured by qRT-PCR. Gain-of-function strategy was used to observe the effect of miR-27b on human umbilical vein endothelial cells (HUVECs) proliferation and migration. Bioinformatics analyses were applied to predict miR-27b targets and then we verified Smad7 by a luciferase reporter assay. Western blot was performed to detect the protein expression of Smad7, PCNA, MMP9, MMP12 and TGF-β-related genes. Results: We confirmed that miR-27b was shown to be dramatically up-regulated in KD serum and KD serum-treated HUVECs and that elevated expression of miR-27b suppressed the proliferation and migration of HUVECs. Furthermore, our results verified that miR-27b mediated cell functions by affecting the TGF-β via targeting Smad7 in HUVECs. Conclusion: These results suggested that up-regulated miR-27b had a protective role in HUVECs proliferation and migration via targeting Smad7 and affecting TGF-β pathway. Therefore, miR-27b represented a potential biomarker for KD and may serve as a promising therapeutic target for KD treatment.

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