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Per-Ola Carlsson

Publications and source records attributed to Per-Ola Carlsson.

At least 19 recordsLinked to original sources
PubMed2006

Revascularization of transplanted pancreatic islets following culture with stimulators of angiogenesis.

BACKGROUND: Insufficient revascularization of transplanted islets may result in chronic hypoxia and loss of islet function. This study investigated whether simple culture of islets with angiogenic substances before transplantation could improve graft revascularization. METHODS: Mouse islets were cultured with vascular endothelial growth factor (VEGF; 20 ng/ml), fibroblast growth factor 2 (FGF-2; 20 ng/ml) or matrix metalloproteinase 9 (MMP-9; 1 mug/ml). Thereafter, 250 islets were implanted beneath the renal capsule of syngeneic C57Bl/6 mice. One month posttransplantation, blood flow (laser-Doppler flowmetry), oxygen tension (Clark microelectrodes), and vascular density were measured and correlated to graft function. RESULTS: Treatment of islets with VEGF during culture caused islet blood vessels to dilate, whereas FGF-2 treatment induced endothelial cell proliferation. However, the number of capillaries in both cases decreased during culture. When investigated one month posttransplantation, both VEGF and FGF-2 pretreated islets had similar or worse vascular engraftment when compared to transplanted control islets. MMP-9 pretreatment of islets increased vascular density, blood flow and oxygen tension within the grafts. Animals receiving MMP-9 pretreated islets returned, however, more slowly to normoglycemia than control animals, and performed worse than controls in a glucose tolerance test one month posttransplantation. CONCLUSIONS: Treatment of islets during culture with VEGF or FGF-2 changed the islet vascular phenotype, but capillaries were still lost. Notably, the number of capillaries in the grafted islets one month posttransplantation was in all cases strikingly similar to that observed prior to transplantation. MMP-9 pretreatment of islets elicited an angiogenic response, which improved revascularization of the transplanted islets.

Angiogenesis Inducing Agents↗
PubMed2006

Islet endothelial cells and pancreatic beta-cell proliferation: studies in vitro and during pregnancy in adult rats.

The growth of both tumors and nonneoplastic tissues may be influenced by signals from the vascular endothelium. In the present investigation we show that purified proliferating endothelial cells from pancreatic islets can stimulate beta-cell proliferation through secretion of hepatocyte growth factor (HGF). This secretion could be induced by soluble signals from the islets, such as vascular endothelial growth factor-A (VEGF-A) and insulin. During pregnancy, the pancreatic beta-cells display a highly reproducible physiological proliferation. We show that islet endothelial cell proliferation precedes beta-cell proliferation in pregnant animals. Vascular growth was closely associated with endocrine cell proliferation, and prominent expression of HGF was observed in islet endothelium on d 15 of pregnancy, i.e. coinciding with the peak of beta-cell proliferation. In summary, our results suggest the existence of an endothelial-endocrine axis within adult pancreatic islets, which is of importance for adult beta-cell proliferation.

Animals↗
PubMed2006

Diabetes-induced decrease in renal oxygen tension: effects of an altered metabolism.

During conditions with experimental diabetes mellitus, it is evident that several alterations in renal oxygen metabolism occur, including increased mitochondrial respiration and increased lactate accumulation in the renal tissue. Consequently, these alterations will contribute to decrease the interstitial pO2, preferentially in the renal medulla of animals with sustained long-term hyperglycemia.

Animals↗
PubMed2006

The pancreatic islet endothelial cell: emerging roles in islet function and disease.

The pancreatic islets are one of the most vascularized organs of the body. This likely reflects the requirements of the organ for a rich supply of nutrients and oxygen to the tissue, as well as the need for rapid disposal of metabolites and secreted hormones. The islet endothelium is richly fenestrated to facilitate trans-endothelial transport of secreted hormones, has a unique expression of surface markers, and produces a number of vasoactive substances and growth factors. The islet endothelial cells play a critical role in the early phase of type 1 diabetes mellitus by increasing the expression of surface leucocyte-homing receptors, thereby enabling immune cells to enter the endocrine tissue and cause beta-cell destruction. Following transplantation, pancreatic islets lack a functional capillary system and need to be properly revascularized. Insufficient revascularization may severely affect the transport properties of the islet endothelial system, resulting in a dysfunctional islet graft.

Journal Article↗
PubMed2006

Perinatal development of the pancreatic islet microvasculature in rats.

The aim of the present study was to investigate possible changes in the islet microvasculature during the period of pronounced beta-cell growth seen perinatally in rats. We studied islet endothelial and beta-cell proliferation, as well as islet vascular density, in rats during this period. There was a progressive increase in islet vascular density from day -1 to day 7 postpartum, with values similar to those in adult rats seen at the latter time point. (3)H-thymidine-labelled islet endothelial cells were extremely rare in adult rats, whereas such cells were much more frequent perinatally. The beta-cell labelling index was higher in all perinatal animals than in adult rats, with peak values seen on day 2. The proliferating endocrine cells were located very close to blood vessels at day 2 after birth. In conclusion, the pronounced growth of islet endocrine cells seen during the first week after birth coincides and co-localizes with an even more pronounced increase in islet endothelial cell proliferation, which results in a marked increase in intra-islet vascular density. This perinatal increase in islet blood vessel density may facilitate glucose sensing and islet hormonal delivery to the systemic circulation.

Animals↗
PubMed2006

Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes.

We identified an angiotensin-generating system in pancreatic islets and found that exogenously administered angiotensin II, after binding to its receptors (angiotensin II type 1 receptor [AT1R]), inhibits insulin release in a manner associated with decreased islet blood flow and (pro)insulin biosynthesis. The present study tested the hypothesis that there is a change in AT1R expression in the pancreatic islets of the obesity-induced type 2 diabetes model, the db/db mouse, which enables endogenous levels of angiotensin II to impair islet function. Islets from 10-week-old db/db and control mice were isolated and investigated. In addition, the AT1R antagonist losartan was administered orally to 4-week-old db/db mice for an 8-week period. We found that AT1R mRNA was upregulated markedly in db/db islets and double immunolabeling confirmed that the AT1R was localized to beta-cells. Losartan selectively improved glucose-induced insulin release and (pro)insulin biosynthesis in db/db islets. Oral losartan treatment delayed the onset of diabetes, and reduced hyperglycemia and glucose intolerance in db/db mice, but did not affect the insulin sensitivity of peripheral tissues. The present findings indicate that AT1R antagonism improves beta-cell function and glucose tolerance in young type 2 diabetic mice. Whether islet AT1R activation plays a role in the pathogenesis of human type 2 diabetes remains to be determined.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Inhibition of p38 MAP kinase in the early posttransplantation phase redistributes blood vessels from the surrounding stroma into the transplanted endocrine tissue.

Transplanted pancreatic islets attain a chronically decreased vascular density following transplantation, despite the increased concentrations of vascular endothelial growth factor (VEGF) secreted from beta-cells in response to hypoxia during culture and in the immediate posttransplantation phase. VEGF, however, exerts dual effects on endothelial cells, and in islet endothelial cells of the adult, the vascular permeability-inducing effects of VEGF seem normally more pronounced than those to induce angiogenesis. p38 MAP kinase activity has recently been shown to serve as a switch to separate these properties of VEGF; inhibition of p38 MAP kinase activity enhances VEGF-induced angiogenesis and, at the same time, abrogates VEGF-induced vascular permeability. We hypothesized that the revascularization of transplanted islets may be hampered by a predisposition of adult islet endothelial cells to react to VEGF by forming fenestrae rather than migrating and proliferating. We therefore administered the p38 MAP kinase inhibitor SB203580 by daily IP injections for the first 14 days following transplantation, and then studied the influence of this treatment on the oxygen tension, blood perfusion, and vascular density of the islet grafts 1 month posttransplantation. SB203580 treatment redistributed islet graft blood vessels from the stroma into the endocrine tissue, and this redistribution of blood vessels into the endocrine tissue was accompanied by an increased oxygenation of the islet cells. However, the total number of blood vessels in the tissue was not affected. The blood perfusion of the islet grafts was also similar in control and SB203580-treated animals. Our results suggest that effects of VEGF to preferentially induce vascular permeability may partially contribute to, but is not the main cause of, low revascularization of transplanted islets.

Animals↗
PubMed2006

Size-dependent revascularization of transplanted pancreatic islets.

For their survival and optimal function, pancreatic islets depend posttransplantation on a rapid and adequate revascularization. Native islets display a marked size-dependent heterogeneity in both angioarchitecture and degree of blood perfusion. This study evaluated whether there also are differences in the degree of revascularization of islets of different size when transplanted. Mouse pancreatic islets were isolated by collagenase digestion, and cultured in vitro for 4-7 days before transplantation. Groups of 200 islets with a diameter either exceeding or being below 100 microm were implanted beneath the left renal capsule of syngeneic C57 BL/6 mice. One month posttransplantation, graft-bearing kidneys were removed. Histological specimens were prepared and stained for endothelium with the lectin Bandeiraea simplicifolia. Pancreata from nontransplanted control animals were prepared similarly. The vascular density in transplanted islets was markedly lower than in native islets. However, islet transplants composed of small islets (<100 microm in diameter) had a vascular density in the endocrine tissue twice that in transplants of larger islets (>100 microm). The connective tissue stroma surrounding smaller islets was also more revascularized than in corresponding grafts with large islets. The vascular density in the connective tissue stroma surrounding the individual islets in the grafts was markedly higher than in the endocrine parts per se. These combined observations indicate that smaller islets have a higher capacity to stimulate regrowth of blood vessels following transplantation. Further studies on islet differences with regard to revascularization capacity may teach us strategies for treatment of transplanted islets to improve their revascularization.

Animals↗
PubMed2005

Endothelial cells in endogenous and transplanted pancreatic islets: differences in the expression of angiogenic peptides and receptors.

BACKGROUND/AIMS: An important reason for the large amount of islets required for successful islet transplantation is likely to be inadequate engraftment of the transplanted islets. Thus, the revascularization is of major importance for graft survival. In order to study the expression of angiogenic peptides and receptors on islet endothelial cells (EC), we needed methods giving access to such endothelium. Therefore, we developed methods to isolate EC from islets transplanted intraportally or beneath the kidney capsule. METHODS: Pancreatic islets were isolated, cultured and syngeneically transplanted into the liver or beneath the kidney capsule of C57BL/6 mice. One month post-transplantation, the islets were retrieved and EC from these islets were explanted. EC were also collected from freshly isolated and cultured non-transplanted islets. The EC were purified with Dynabeads and identified with immunocytochemistry. Angiogenesis GEArray technology was used to study angiogenic gene expression. RESULTS: Several angiogenic genes were expressed in EC; e.g. endostatin, pigment-epithelial derived factor, vascular endothelial growth factor and angiopoietin-2, and their expression were affected by culture. CONCLUSION: The expression of angiogenesis-related genes in islet EC from non-transplanted islets is affected by culture. Moreover, we also describe a technique, which makes it possible to obtain EC from transplanted islets.

Animals↗
PubMed2005

The pancreatic islet endothelial cell: emerging roles in islet function and disease.

The pancreatic islets are one of the most vascularized organs of the body. This likely reflects the requirements of the organ for a rich supply of nutrients and oxygen to the tissue, as well as the need for rapid disposal of metabolites and secreted hormones. The islet endothelium is richly fenestrated to facilitate trans-endothelial transport of secreted hormones, has a unique expression of surface markers, and produces a number of vasoactive substances and growth factors. The islet endothelial cells play a critical role in the early phase of type 1 diabetes mellitus by increasing the expression of surface leucocyte-homing receptors, thereby enabling immune cells to enter the endocrine tissue and cause beta-cell destruction. Following transplantation, pancreatic islets lack a functional capillary system and need to be properly revascularized. Insufficient revascularization may severely affect the transport properties of the islet endothelial system, resulting in a dysfunctional islet graft.

Animals↗
PubMed2005

Thick ascending tubular cells in the loop of Henle: regulation of electrolyte homeostasis.

Renal medullary tubular cells in the loop of Henle have crucial importance for the regulation of homeostasis of the extracellular fluid. These cells receive limited amount of blood and oxygen, and are also constantly challenged by the hypertonic environment. The medullary tubular cells in the last part of the loop of Henle have one of the highest known contents of mitochondria of all mammalian cells, reflecting their need for oxidative metabolism in order to sustain high ATP production for active transepithelial electrolyte transport. The commonly used diureticum furosemide targets one of the transporters present in these tubular cells with resulting diuresis. Several pathological states are associated with altered function of the medullary tubular cells, and the nephrotoxic substances tacrolimus and cyclosporine act on these cells. The specific Tamm-Horsfall glycoprotein is produced by medullary tubular cells. Alteration in the urinary excretion of this protein is used as marker of tubular damage.

Animals↗
PubMed2005

Pancreatic islet renin angiotensin system: its novel roles in islet function and in diabetes mellitus.

Several regulatory systems are implicated in the regulation of islet function and beta cell mass. Of great interest in this context are some endocrine, paracrine/autocrine, and intracrine regulators. These include, to name but a few, the gut peptides, growth factors, prostaglandins, and some vasoactive mediators such as nitric oxide, bradykinins, endothelins, and angiotensins. Apart from its potent vasoconstrictor actions, the renin-angiotensin system (RAS) that generates angiotensin II has several novel functions-stimulation and inhibition of cell proliferation; induction of apoptosis; generation of reactive oxygen species; regulation of hormone secretion; and proinflammatory and profibrogenic actions. In the pancreas, recent evidence supports the presence of an islet RAS, which is subject to activation by islet transplantation and diabetes. Such a local islet RAS, if activated, may drive islet fibrosis and reduce islet blood flow, oxygen tension, and insulin biosynthesis. Moreover, activation of an islet RAS may drive the synthesis of reactive oxygen species, cause oxidative stress-induced beta cell dysfunction and apoptosis, and thus contribute to the islet dysfunction seen in type 2 diabetes and after islet transplantation. Blockade of the RAS could contribute to the development of novel therapeutic strategies in the prevention and treatment of patients with diabetes and in islet transplantation.

Animals↗
PubMed2005

The effects of carbon dioxide versus ioxaglate in the rat kidney.

PURPOSE: The renal medulla seems to be particularly vulnerable to vascular injection of iodinated contrast media, particularly in patients with preexisting renal dysfunction. The gas carbon dioxide is frequently used as an alternative to iodinated contrast medium in these patients. In this study, the renal effects of CO(2) are investigated and compared with those of the iodinated contrast medium ioxaglate. MATERIALS AND METHODS: Cortical and outer medullary blood flow (measured by laser Doppler flowmetry) and oxygen tension (Po(2); measured by oxygen microelectrodes) were recorded in anesthetized Sprague-Dawley rats given an intraarterial injection of ioxaglate (320 mgI/kg body weight), a volume-matched dose of CO(2), or Ringer solution. RESULTS: Injection of CO(2) induced a pronounced and transient decrease in cortical blood flow and Po(2) (approximately -45%), whereas outer medullary blood flow and Po(2) were transiently increased (+21% and +29%, respectively). In contrast, injection of ioxaglate did not influence cortical blood flow and caused outer medullary blood flow to decrease by 17%. Ioxaglate injection also resulted in a decrease in cortical and outer medullary Po(2) (-15% and -33%, respectively). Ringer solution affected none of the recorded parameters. CONCLUSIONS: Although injection of CO(2) markedly affected regional renal blood flow and Po(2), there were qualitatively different effects in the cortex and outer medulla compared with those seen after injection of ioxaglate. The pronounced decrease in medullary blood flow and Po(2) observed after injection of ioxaglate was absent in the animals injected with CO(2). This might suggest beneficial effects of the use of CO(2) instead of iodinated contrast media in patients with increased risk of developing renal failure.

Animals↗
PubMed2005

Pancreatic islet function in a transgenic mouse expressing fluorescent protein.

Pancreatic islet function and glucose homeostasis have been characterized in the transgenic YC-3.0 mouse, which expresses the yellow chameleon 3.0 (YC-3.0) protein under the control of the beta-actin and the cytomegalovirus promoters. Fluorescence from the enhanced yellow fluorescent protein (EYFP), one part of the yellow chameleon protein, was used as a reporter of transgene expression. EYFP was expressed in different quantities throughout most cell types, including islet endocrine and stromal cells. No adverse effects of the transgene on animal health, growth or fertility were observed. Likewise, in vivo glucose homeostasis, mean arterial blood pressure and regional blood flow values were normal. Furthermore, the transgenic YC-3.0 mouse had a normal beta-cell volume and mass as well as glucose-stimulated insulin release in vitro, compared with the C57BL/6 control mouse. Isolated islets from YC-3.0 animals continuously expressed the transgene and reversed hyperglycemia when transplanted under the renal capsule of alloxan-diabetic nude mice. We conclude that isolated pancreatic islets from YC-3.0 animals implanted into recipients without any EYFP expression, constitute a novel and versatile model for studies of islet engraftment.

Animals↗
PubMed2005

Reduced nitric oxide concentration in the renal cortex of streptozotocin-induced diabetic rats: effects on renal oxygenation and microcirculation.

Nitric oxide (NO) regulates vascular tone and mitochondrial respiration. We investigated the hypothesis that there is reduced NO concentration in the renal cortex of diabetic rats that mediates reduced renal cortical blood perfusion and oxygen tension (P O2). Streptozotocin-induced diabetic and control rats were injected with l-arginine followed by Nomega-nitro-L-arginine-metyl-ester (L-NAME). NO and P O2 were measured using microsensors, and local blood flow was recorded by laser-Doppler flowmetry. Plasma arginine and asymmetric dimethylarginine (ADMA) were analyzed by high-performance liquid chromatography. L-Arginine increased cortical NO concentrations more in diabetic animals, whereas changes in blood flow were similar. Cortical P O2 was unaffected by L-arginine in both groups. L-NAME decreased NO in control animals by 87 +/- 15 nmol/l compared with 45 +/- 7 nmol/l in diabetic animals. L-NAME decreased blood perfusion more in diabetic animals, but it only affected P O2 in control animals. Plasma arginine was significantly lower in diabetic animals (79.7 +/- 6.7 vs. 127.9 +/- 3.9 mmol/l), whereas ADMA was unchanged. A larger increase in renal cortical NO concentration after l-arginine injection, a smaller decrease in NO after L-NAME, and reduced plasma arginine suggest substrate limitation for NO formation in the renal cortex of diabetic animals. This demonstrates a new mechanism for diabetes-induced alteration in renal oxygen metabolism and local blood flow regulation.

Animals↗
PubMed2005

Changes in graft blood flow early after syngeneic rat pancreas-duodenum transplantation.

Organ transplantation is associated with changes in graft blood flow, both acutely caused by reperfusion associated phenomena, and chronically due to e.g. denervation. The aim of the study was to investigate regional blood flow early after implantation of a syngeneic pancreas-duodenum transplant in rats, i.e. during reperfusion. Warm ischemia time was 1-2 min and cold ischemia 90 min. Blood flow values were measured with coloured microspheres both 10 and 30 min after implantation in transplanted rats, and at one time point in control rats. A marked decrease in the blood perfusion of the transplanted duodenum compared to the endogenous intestine was seen at both 10 and 30 min. Total graft pancreatic blood flow was increased both 10 and 30 min after implantation, whilst islet blood flow remained unchanged compared to the endogenous gland. We conclude that the blood perfusion of the graft is markedly changed in the immediate post-transplantation period, presumably due to reperfusion. However, islet blood perfusion remains constant, suggesting that islet vasculature is less sensitive to changes induced by the implantation.

Animals↗
PubMed2005

Acute effects of a 50% partial pancreatectomy on total pancreatic and islet blood flow in rats.

OBJECTIVES: The aim of the study was to investigate how an acute increase in functional demand for insulin release affected islet blood perfusion in anesthetized rats. METHODS: We measured total pancreatic and islet blood flow with differently colored microspheres before and 30 minutes after a 50% partial pancreatectomy. RESULTS: The blood glucose concentrations increased in the animals subjected to partial pancreatectomy. The fact that serum insulin concentrations remained unaffected implies that the islets in fact doubled their output of insulin to maintain the same degree of insulinemia. Still, pancreatic islet blood flow was the same as in the sham-operated animals. Likewise, the number of perfused pancreatic islets and the flow distribution between individual islets were not influenced by the partial pancreatectomy. CONCLUSIONS: We conclude that the acute demand for insulin secretion induced by a 50% partial pancreatectomy is not necessarily associated with an acute increase in islet blood perfusion. These findings suggest that basal islet blood flow is high enough to allow for short-term changes in hormone release without simultaneous changes in blood perfusion.

Anesthesia↗