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  • In the vasculature it is known that

    2022-11-30

    In the vasculature, it is known that A2A and A2B adenosine receptors are stimulatory for adenylyl-cyclase, leading to cyclic-AMP (cAMP) production and vasodilation, while the A1 and A3 adenosine receptors are linked to the inhibitory Gi, suppressing adenylyl-cyclase and favoring contraction. However, studies have shown that pathways associated with increased vascular contraction, such as PKC and MAPK, can also be activated by A2A and A2B adenosine receptors. This was shown to be independent of Gs and was dependent upon Gi or Gq activation (Cohen et al., 2010; Schulte and Fredholm, 2003). The ability of theses receptors to potentially trigger multiple signaling pathways is intriguing and raises the question of if these signaling pathways are tissue specific and whether disease states, such as hypertension or diabetes, can favor one pathway over another. This may also explain the contradictory role of these receptors in attenuating versus exacerbating the disease (Tak et al., 2014, Zhang et al., 2013). Thus, it is imperative to study adenosine signaling in disease states to understand their contribution to the amelioration or exacerbation of the disease. In an STZ-treated animal model,A1 adenosine receptor SBI-0206965 australia was increased in the kidney (Pawelczyk et al., 2005), while its expression in pancreatic α-cells was diminished in a non obese diabetic mouse model (Yip et al., 2013), suggesting that its expression may be affected in diabetes. In the present study, we did not see a difference in A1 adenosine receptor expression in the aorta, although the vascular response to A1 adenosine receptor agonist was attenuated in aortic rings from diabetic mice. This may be a result of altered A1 adenosine receptor signaling through decreased A1 adenosine receptor sensitivity to its agonist or its coupling to Gi, which was shown to be impaired in T1D (Barrington et al., 1996, Green and Johnson, 1991). In addition, T1D was shown to be associated with a decreased expression of Gi in rat hepatocytes, which may also result in decreased A1 adenosine receptor signaling (Gawler et al., 1987). In addition, posttranslational modifications that are associated with diabetes, such as O-Glc-N-acylation, may also affect receptor signaling.
    Conclusion Other studies have shown that, despite apparent vascular dysfunction, blood pressure in STZ-treated animals is not significantly different from that of control animals (Nacci et al., 2009, Tojo et al., 2016). In this study, we showed that vascular A1 adenosine receptor signaling was reduced in diabetes, and this may be due to a compensatory mechanism to counteract increased vascular contractility observed in diabetes and prevent increases in blood pressure (see Fig. 6). Our present study also showed a disconnect between receptor expression and signaling, which has also been previously shown by others (Bender et al., 2009). Thus, future studies investigating post-translational modifications and/or downstream receptor signaling pathways are crucial to understanding the potential role of the A1adenosine receptor and may explain the discrepancy observed between adenosine receptor expression and signaling in cardiovascular physiology and pathophysiology.
    Acknowledgments
    Introduction The blockade of abnormal angiogenesis in pathological conditions such as diabetes, tumor is gaining lot of significance during drug development. Abnormal angiogenesis was observed under numerous conditions such as solid tumour growth, diabetic retinopathy, psoriasis and rheumatoid arthritis [[1], [2], [3]]. Angiogenesis proceeds with capillary formation and initiation of sprouting in response to diverse cytokines and metabolic stimulus. Vascular Endothelial Growth Factor (VEGF), an important regulator of normal and pathological angiogenesis [4]. It is released immediately after the angiogenic stimuli and signals vascular endothelial cells proliferation and migration to form new capillary tubes. More recently, the interactions between Notch signaling pathway and VEGF have been described during angiogenesis as VEGF is known to induce expression of Notch receptors and ligands in a gradient dependent manner [5]. Nude mice study with targeted deletions of NOTCH1 and DLL4 resulted in death due to defects in proper formation of angiogenic vascular remodeling failure. Notch was reported to be in feedback loop link with VEGF, that upregulates DLL4 by VEGF in development and angiogenesis [6]. VEGF is highly regulated by hypoxia through adenosine receptors and HIF1a, which can react with hypoxia response elements and induce transcriptional activity. Therefore SBI-0206965 australia VEGF is focused as a potential target for treatment of various tumors and angiogenic disorders under hypoxic condition [7,8].