Vascular Proliferation and Enhanced Expression of Endothelial Nitric Oxide Synthase in Human Peritoneum Exposed to Long-Term Peritoneal Dialysis

Abstract

Abstract. Long-term peritoneal dialysis (PD) is associated with alterations in peritoneal permeability and loss of ultrafiltration. These changes originate from increased peritoneal surface area, but the morphologic and molecular mechanisms involved remain unknown. The hypothesis that modifications of activity and/or expression of nitric oxide synthase (NOS) isozymes might play a role in these modifications, via enhanced local production of nitric oxide, was tested in this study. NOS activities were measured by the L-citrulline assay in peritoneal biopsies from seven control subjects, eight uremic patients immediately before the onset of PD, and 13 uremic patients on short-term (<18 mo,n= 6) or long-term (>18 mo,n= 7) PD. Peritoneal NOS activity is increased fivefold in long-term PD patients compared with control subjects. In uremic patients, NOS activity is positively correlated with the duration of PD. Increased NOS activity is mediated solely by Ca2+-dependent NOS and, as shown by immunoblotting, an upregulation of endothelial NOS. The biologic relevance of increased NOS in long-term PD was demonstrated by enhanced nitrotyrosine immunoreactivity and a significant increase in vascular density and endothelial area in the peritoneum. Immunoblotting and immunostaining studies demonstrated an upregulation of vascular endothelial growth factor (VEGF) mostly along the endothelium lining peritoneal blood vessels in long-term PD patients. In the latter, VEGF colocalized with the advanced glycation end product pentosidine deposits. These data provide a morphologic (angiogenesis and increased endothelial area) and molecular (enhanced NOS activity and endothelial NOS upregulation) basis for explaining the permeability changes observed in long-term PD. They also support the implication of local advanced glycation end product deposits and liberation of VEGF in that process.

Vascular endothelial growth factor-mediated peritoneal neoangiogenesis in peritoneal dialysis

“…These transdifferentiated PMCs are located, at least in part, and embedded in the submesothelial area due to their increased migratory capacity. 94,95 In addition, other immunostaining studies also provide clear evidence for the local production of VEGF in PMCs, 13,34,71,96 demonstrating that mesothelial cells are the main source of VEGF in the peritoneal cavity.…”

“…[10][11][12] The possible explanation is that the biocompatible solutions reduce the production of vasoactive substances, which might significantly affect blood flow and the permeability of the peritoneal vascular bed. 13 Collectively, these data suggested that long-term PD provoked great changes in the peritoneal vasculature. This review will focus on the role of vascular endothelial growth factor (VEGF) in regulating the peritoneal neoangiogenesis in PD and the potential clinical application of antiangiogenic drugs targeted on VEGF in PD.…”

“…Several reports have clarified that uremic patients are more likely to develop microvascular dysfunction and angiogenesis. 13,[43][44][45] Uremia has the ability to upregulate the expression of VEGF-C in gene and protein levels in uremic rat 46 and increase microvessel density. 47 In addition, different primary diseases of ESRD (i.e.…”

How to Improve the Biocompatibility of Peritoneal Dialysis Solutions (without Jeopardizing the Patient’s Health)

“…Experimental studies in a rat model of PD showed that exposure to amino acid PD fluid was associated with a reduced peritoneal AGE deposition, lower levels of vascular endothelial growth factor, and a lower vessel density compared to treatment with standard glucose-based PD solutions [ 93 ]. However, in human peritoneal mesothelial cells cultured with amino-acid-containing PD dialysate, there was increased generation of nitric oxide [ 94 ], a finding which may have pathophysiological relevance [ 95 ].…”

Angiogenic Role of Mesothelium-Derived Chemokine CXCL1 During Unfavorable Peritoneal Tissue Remodeling in Patients Receiving Peritoneal Dialysis as Renal Replacement Therapy

“…On the molecular level, VEGF is the best characterized mediator of angiogenesis (28) and it plays a role in peritoneal membrane dysfunction in PD (17,29,30). Prior studies identified the mesothelium as an important source of VEGF in the peritoneum and deciphered pathways of VEGF induction during PD (16,17,(31)(32)(33)(34). However, VEGF is not the only mediator of angiogenesis and prior attempts to inhibit VEGF in cancer revealed the existence of alternative VEGF-independent angiogenic programs, including one that can be initiated by IL-17 (35).…”