Vascular-adrenal Niche - Endothelial Cell-mediated Sensitization of Human Adrenocortical Cells to Angiotensin II

Ansurudeen, Ishrath; Kopprasch, Steffi; Ehrhart‐Bornstein, Monika; Willenberg, Holger S.; Krug, Alexander W.; Funk, R.; Bornstein, S. R.

doi:10.1055/s-2006-948136

Cited by 19 publications

(20 citation statements)

References 23 publications

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“…However, to be metabolically active, the islets require access to oxygen, nutrients, and other metabolites at a physiological pH and with exclusion of toxic metabolites and oxidative stress (26,28,29). As in the early posttransplant setting, revascularization of transplanted islets has not yet occurred, and the islets are supplied with oxygen by diffusion only; close proximity to a proper vascular system is therefore essential (12,30). Ideally, islets should be transplanted into a site with high oxygen tension.…”

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confidence: 99%

“…The adrenal gland may offer the unique features favoring its use as a transplantation site for pancreatic islets because of high oxygen tension through a dense vascularization (30), a high endothelial cell content, and a local anti-inflammatory and immunoprotective environment (31,32). Furthermore, findings derived from model organisms have shown a direct relationship between the degree of hyperglycemia and adrenal cortical function and steroidogenesis (33).…”

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confidence: 99%

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Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone

Schubert

Schmid

Lehmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Here, we evaluate an alternative approach of preconditioning pancreatic islets before transplantation using a potent agonist of growth-hormone-releasing hormone (GHRH) to promote islet viability and function, and we explore the adrenal gland as an alternative transplantation site for islet engraftment. The endocrine microenvironment of the adrenal represents a promising niche with the unique advantages of exceptional high oxygen tension and local antiinflammatory and immunosuppressive properties. GHRH agonists have been shown to promote islet graft survival and function, which may help to reduce the islet mass necessary to reverse diabetes. In the present study, the most potent GHRH agonist MR403 was tested on insulinoma cells, isolated rat islets, and adrenal β-cell cocultures in vitro. GHRH receptor is expressed on both adrenal cells and islets. MR403 caused a significant increase in cell viability and proliferation and revealed an antiapoptotic effect on insulinoma cells. Viability of rat islets was increased after treatment with the agonist and in coculture with adrenal cells. Rat islets were transplanted into diabetic mice to the intraadrenal transplant site and compared with the classical transplants underneath the kidney capsule. Graft function and integration were tested by metabolic follow-up and immunohistochemical staining of intraadrenal grafts. A rapid decrease occurred in blood glucose levels in both models, and all animals reached normoglycemia within the first days after transplantation. Our studies demonstrated that the adrenal may be an attractive site for islet transplantation and that GHRH analogs might allow reduction of the islet mass needed to reverse a diabetic status.β-cell replacement | regenerative therapy | type 1 diabetes mellitus

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confidence: 99%

mentioning

confidence: 99%

Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone

Schubert

Schmid

Lehmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In line with our findings, ECCM has been shown to stimulate adrenal cellderived aldosterone production. 4,[23][24][25] This phenomenon was neither inhibited by Ang II nor by endothelin blockers, yet was subject to proteolysis and heat inactivation 26 and could well be locally, in the ECs, produced VEGF.…”

Section: Discussionmentioning

confidence: 99%

“…EC-conditioned medium (ECCM) was generated by incubating the cultured HUVECs with serum-free EBM-2 or DMEM-F12 containing insulin, transferrin, sodium selenite (ITS) with/without vascular endothelial growth factor (VEGF, 50 ng/mL) for 24 hours. 4 …”

Section: Conditioning Of Ec Supernatantmentioning

confidence: 99%

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Vascular Endothelial Growth Factor-A and Aldosterone

et al. 2013

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Abstract-Aldosterone levels are markedly elevated during normal pregnancy but fall even though volume contracts when preeclampsia occurs. The level of aldosterone in either condition cannot be explained solely by the activity of the renin-angiotensin II system. In normal gestation, vascular endothelial growth factor (VEGF) is thought to maintain vascular health, but its role in adrenal hormone production is unknown. We hypothesized that the role of VEGF in the adrenal gland is to maintain vascular health and regulate aldosterone production. Here, we demonstrate that supernatant of endothelial cells grown in the presence of VEGF enhanced aldosterone synthase activity in human adrenocortical cells. VEGF either alone or combined with angiotensin II increased aldosterone production in adrenal cells. These data suggest that endothelial cell-dependent and independent activation of aldosterone is regulated by VEGF. In contrast to angiotensin II, VEGF did not upregulate the steroidogenic acute regulatory protein. Consistent with this observation, angiotensin II stimulated both aldosterone and cortisol synthesis from progesterone, whereas VEGF stimulated selectively aldosterone production. In rats, overexpression of soluble fms-like tyrosine kinase-1, an endogenous VEGF inhibitor, led to adrenocortical capillary rarefaction and fall in aldosterone concentrations that correlated inversely with soluble fms-like tyrosine kinase-1 levels. These findings may explain why aldosterone increases so markedly during normal gestation and why preeclampsia, a condition characterized by high soluble fms-like tyrosine kinase-1, is associated with inappropriately low aldosterone levels in spite of relatively lower plasma volumes. (Hypertension. 2013;61:1111-1117.) • Online Data SupplementKey Words: adrenal cell ■ aldosterone ■ aldosterone synthase ■ preeclampsia ■ soluble fms-like tyrosine kinase-1 ■ steroidogenic acute regulatory protein ■ vascular endothelial growth factor

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Evidence for the involvement of endothelial cell products in adrenal CITED2 expression

et al. 2009

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The adrenal gland contains a well-organized network of blood vessels, and adrenocortical cells are situated in close proximity to endothelial cells. Recently, several new mechanisms have been characterized that control the release of aldosterone by adrenocortical cells, including the involvement of endothelial-cell-derived factors. Interestingly, a CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), which is necessary for adrenal development, has been linked to aldosterone synthesis. We have therefore examined the effects of endothelial-cell-conditioned medium (ECCM), as produced during the incubation of human umbilical vein endothelial cells for 24 h, on the promoter activity and mRNA and protein expression of CITED2 in adrenocortical cells as represented by the NCI-H295R cell line. We have found a dose-dependent effect of ECCM on CITED2 promoter activity; this peaks at 480%. Activation of the CITED2 promoter occurs in parallel to an increase in CITED2 messenger RNA (as quantified by real-time polymerase chain reaction) and protein. The stimulatory effect of ECCM can be reversed by blocking mitogen-activated protein kinase activity with the MEK1-inhibitor PD98059. We conclude that products secreted by endothelial cells control not only steroidogenesis, but also factors that are important for adrenocortical development, thereby highlighting the role of cellular interactions within adrenocortical development and physiology.

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Vascular-adrenal Niche - Endothelial Cell-mediated Sensitization of Human Adrenocortical Cells to Angiotensin II

Cited by 19 publications

References 23 publications

Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone

Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone

Vascular Endothelial Growth Factor-A and Aldosterone

Evidence for the involvement of endothelial cell products in adrenal CITED2 expression

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