Beneficial Role of Pancreatic Microenvironment for Angiogenesis in Transplanted Pancreatic Islets

Abstract

Pancreatic islets implanted heterotopically (i.e., into the kidney, spleen, or liver) become poorly revascularized following transplantation. We hypothesized that islets implanted into the pancreas would become better revascularized. Islets isolated from transgenic mice expressing enhanced yellow fluorescent protein (EYFP) in all somatic cells were cultured before they were implanted into the pancreas or beneath the renal capsule of athymic mice. Vascular density was evaluated in histological sections 1 month posttransplantation. EYFP was used as reporter for the transgene to identify the transplanted islets. Islet endothelial cells were visualized by staining with the lectin Bandeiraea simplicifolia (BS-1). Capillary numbers in intrapancreatically implanted islets were only slightly lower than those counted in endogenous islets, whereas islets implanted beneath the renal capsule had a markedly lower vascular density. In order to determine if this high graft vascular density at the intrapancreatic site reflected expansion of remnant donor endothelial cells or increased ingrowth of blood vessels from the host, also islets from Tie2-green fluorescent protein (GFP) mice (i.e., islets with fluorescent endothelial cells) were transplanted into the pancreas or beneath the renal capsule of athymic mice. These islet grafts revealed that the new vascular structures formed in the islet grafts contained very few GFP-positive cells, and thus mainly were of recipient origin. The reason(s) for the much better ingrowth of blood vessels at the intrapancreatic site merits further studies, because this may help us form strategies to overcome the barrier for ingrowth of host vessels also into islets in heterotopic implantation sites.

α-cell loss from islet impairs its insulin secretion in vitro and in vivo

“…22 As the original islet capillary network is injured during islet isolation and culture, 23,24 a process of islet re-vascularization is needed after islet transplantation. However, it has been demonstrated that the newly-formed islet microvascular endothelial cells after re-vascularization are of host origin, 25 and may be devoid of the self-protection mechanism due to lack of α-1 proteinase inhibitor expression. Second, pancreatic islets are densely innervated and controlled by the autonomic nervous system that modulates islet blood flow and insulin secretion.…”

Effect of renin angiotensin system blockade on the islet microvessel density of diabetic rats and its relationship with islet function

“…Many studies have suggested multiple interactions between islet endothelial cells and β cells besides those involved in the regulation of blood perfusion and transport processes over the capillary wall [21] . A recent study treated adult mice with different VEGF-neutralizing agents and demonstrated that neutralization of VEGF activity resulted in, not only a thickening of the endothelial cells and loss of fenestrations, but also a 45%-70% decrease in islet blood vessel density [22] .…”

Oxygenation of islets and its role in transplantation

“…Improved islet graft revascularization may also be achieved by change of implantation organ. We have recently investigated the intrapancreatic site and found an almost normalized islet vascular network at 1 month posttransplantation [48 ]. This finding reflected an increased ingrowth of recipient blood vessels rather than an expansion of remnant blood vessels in the donor tissue.…”