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Delayed branching of endothelial capillary-like cords in glycated collagen I is mediated by early induction of PAI-1.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Chen, J. Brodsky, Sergey V. Li, Hongping Hampel, Dierk J. Miyata, Toshio Weinstein, Talia Gafter, Uzi Norman, Jill T. Fine, Leon G. Goligorsky, Michael S. |
| Copyright Year | 2001 |
| Abstract | Development of micro- and macrovascular disease in diabetes mellitus (DM) warrants a thorough investigation into the repertoire of endothelial cell (EC) responses to diabetic environmental cues. Using human umbilical vein EC (HUVEC) cultured in three-dimensional (3-D) native collagen I (NC) or glycated collagen I (GC), we observed capillary cord formation that showed a significant reduction in branching when cells were cultured in GC. To gain insight into the molecular determinants of this phenomenon, HUVEC subjected to GC vs. NC were studied using a PCR-selected subtraction approach. Nine different genes were identified as up- or downregulated in response to GC; among those, plasminogen activator inhibitor-1 (PAI-1) mRNA was found to be upregulated by GC. Western blot analysis of HUVEC cultured on GC showed an increase in PAI-1 expression. The addition of a neutralizing anti-PAI-1 antibody to HUVEC cultured in GC restored the branching pattern of formed capillary cords. In contrast, supplementation of culture medium with the constitutively active PAI-1 reproduced defective branching patterns in HUVEC cultured in NC. Ex vivo capillary sprouting in GC was unaffected in PAI-1 knockout mice but was inhibited in wild-type mice. This difference persisted in diabetic mice. In conclusion, the PCR-selected subtraction technique identified PAI-1 as one of the genes characterizing an early response of HUVEC to the diabetic-like interstitial environment modeled by GC and responsible for the defective branching of endothelial cells. We propose that an upregulation of PAI-1 is causatively linked to the defective formation of capillary networks during wound healing and eventual vascular dropout characteristic of diabetic nephropathy. |
| Starting Page | R5 |
| Ending Page | R8 |
| Page Count | 4 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://ajprenal.physiology.org/content/ajprenal/281/1/F71.full.pdf |
| PubMed reference number | 11399648v1 |
| Volume Number | 281 |
| Issue Number | 1 |
| Journal | American journal of physiology. Renal physiology |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Collagen Diseases Culture Media Diabetes Mellitus Diabetic Nephropathy Endothelial Cells Endothelium Kidney Diseases Paget's Disease, Mammary Plasminogen Activator SERPINE1 protein, human Subtraction Technique Umbilical vein Umbilicus (Anatomy) Wound Healing |
| Content Type | Text |
| Resource Type | Article |
