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      Angiopoietin-2 Is Associated with Aortic Stiffness in Diabetes Patients in Ghana: A Case-Control Study

      1 , 2 , 1 ,
      International Journal of Vascular Medicine

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          Impaired angiogenesis, measured as serum levels of angiogenic growth factors, may be among the mechanisms underlining aortic stiffness in diabetes patients. We studied the association between aortic stiffness and circulating angiogenic growth factors in type 2 diabetes (T2DM) patients without any organ damage.


          In a case-control design, aortic pulse wave velocity (PWV), augmentation index (AIx), and aortic blood pressures (BPs) were measured in 140 T2DM patients and 110 nondiabetic controls. Fasting blood samples were collected to measure the levels of angiopoietin- (Ang-) 1, Ang-2, and vascular endothelial growth factor-A (VEGF).


          Compared to nondiabetes participants, T2DM patients had increased PWV (8.7 ± 1.5 vs. 7.6 ± 1.3, p = 0.031), aortic pulse BP (58 ± 20 vs. 49 ± 17, p = 0.011), Ang-2 (838 (473–1241) vs. 597 (274–1005), p = 0.018), and VEGF (72.2 (28–201.8) vs. 48.4 (17.4–110.1), p = 0.025) but reduced levels of AIx (21.7 ± 13.8 vs. 34 ± 12.9, p < 0.001) and Ang-1 (33.1 (24.7–42.1) vs. 41.1 (30–57.3), p = 0.01). In all study participants, compared to those in the lower tertile, participants in the upper tertile of Ang-2 had increased odds of PWV (2.01 (1.17–3.84), p = 0.004), aortic systolic BP (1.24 (1.04–1.97), p = 0.011), and aortic pulse BP (1.19 (1.04–1.82), p = 0.041) but reduced odds of AIx (0.84 (0.71–0.96), p = 0.014) in multivariable-adjusted models.


          In our study population, increased circulating Ang-2 was associated with increased levels of aortic stiffness parameters.

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          Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

          The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.
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            Angiopoietins in angiogenesis.

            Tie-1 and Tie-2 tyrosine kinase receptors are expressed specifically on vascular endothelial cells and on a certain subtype of macrophages implicated in angiogenesis, thus, they have been a major focus of angiogenesis research. Tie-1 and Tie-2 are essential for vascular maturation during developmental, physiological and pathological angiogenesis. Angiopoietin 1-4 (Ang-1-4) have been identified as bona fide ligands of the Tie-2 receptor, while Tie-1 remains an orphan receptor which is able to heterodimerize with Tie-2 and to modulate Tie-2 signal transduction. The most exhaustively studied angiopoietins are Ang-1 and Ang-2. Ang-1 is a critical player in vessel maturation and it mediates migration, adhesion and survival of endothelial cells. Ang-2 disrupts the connections between the endothelium and perivascular cells and promotes cell death and vascular regression. Yet, in conjunction with VEGF, Ang-2 promotes neo-vascularization. Hence, angiopoietins exert crucial roles in the angiogenic switch during tumor progression, and increased expression of Ang-2 relative to Ang-1 in tumors correlates with poor prognosis. Its central role in the regulation of physiological and pathological angiogenesis makes the angiopoietin/Tie signaling pathway a therapeutically attractive target for the treatment of vascular disease and cancer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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              Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo.

              Modulation of Tie2 receptor activity by its angiopoietin ligands is crucial for angiogenesis, blood vessel maturation, and vascular endothelium integrity. It has been proposed that angiopoietins 1 (Ang1) and 2 (Ang2) are pro- and anti-angiogenic owing to their respective agonist and antagonist signaling action through the Tie2 receptor. The function of Ang2 has remained controversial, however, with recent reports suggesting that in some circumstances, it may be pro-angiogenic. We have examined this issue using the transient ocular microvessel network called the pupillary membrane as a unique in vivo model for studying the effects of vascular regulators. We show that in vivo, in the presence of endogenous vascular endothelial growth factor (VEGF)-A, Ang2 promotes a rapid increase in capillary diameter, remodeling of the basal lamina, proliferation and migration of endothelial cells, and stimulates sprouting of new blood vessels. By contrast, Ang2 promotes endothelial cell death and vessel regression if the activity of endogenous VEGF is inhibited. These observations support a model for regulation of vascularity where VEGF can convert the consequence of Ang2 stimulation from anti- to pro-angiogenic.

                Author and article information

                Int J Vasc Med
                Int J Vasc Med
                International Journal of Vascular Medicine
                12 October 2023
                : 2023
                : 3155982
                1Department of Physiology, University of Ghana Medical School, Accra, Ghana
                2Medical Laboratory Unit, Mamprobi Hospital, Ghana Health Service, Accra, Ghana
                Author notes

                Academic Editor: Baohui Xu

                Author information
                Copyright © 2023 Jennifer A. Agyekum and Kwame Yeboah.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 8 May 2023
                : 28 September 2023
                : 29 September 2023
                Research Article

                Cardiovascular Medicine
                Cardiovascular Medicine


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