Abstract: SA-PO344
Potent Pro-Angiogenic Mediators Fail to Improve the Post-Ischemic Angiogenesis in the Uremic Milieu
Session Information
- Hypertension and CVD: Mechanisms
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Arinze, Nkiruka, Boston University Medical Center, Boston, Massachusetts, United States
- Richards, Sean, Boston University Medical Center, Boston, Massachusetts, United States
- Napoleon, Marc A., Boston University Medical Center, Boston, Massachusetts, United States
- Walker, Joshua A., Boston University Medical Center, Boston, Massachusetts, United States
- Belghasem, Mostafa, Boston University Medical Center, Boston, Massachusetts, United States
- Lyle, Chimera Lynn, Boston University Medical Center, Boston, Massachusetts, United States
- Anderson, Stephan, Boston University, Boston, Massachusetts, United States
- Siracuse, Jeffrey, Boston University Medical Center, Boston, Massachusetts, United States
- Farber, Alik, Boston University Medical Center, Boston, Massachusetts, United States
- Rahimi, Nader, Boston University Medical Center, Boston, Massachusetts, United States
- Chitalia, Vipul C., Boston University Medical Center, Boston, Massachusetts, United States
Background
Patients with chronic kidney disease (CKD) have been shown to have a 3-fold higher prevalence of peripheral arterial disease. Although CKD represents an independent risk factor for PAD, CKD-specific contributors remain unknown. The Wnt/beta catenin pathway is a potent pro-angiogenic pathway that increases endothelial cell proliferation and capillary permeability. Casitas b-cell lymphoma (c-Cbl) is a negative regulator of nuclear active beta catenin. We hypothesized that reduced activity of c-Cbl is likely to augment Wnt/beta catenin signaling in ischemia-induced angiogenesis in the uremic milieu.
Methods
Unilateral hindlimb ischemia (HLI) model was performed in 8-12 week old c-Cbl +/+ and c-Cbl +/- female mice under non-CKD and CKD conditions using the adenine-induced CKD model. Laser Doppler imaging was used to determine perfusion recovery over time. CD31 staining was used to determine capillary density. Capillary leakage was detected by dextran infusion. Both were quantitated as integrated density. Wnt/beta catenin activity was examined in primary human endothelial cells.
Results
On normal diet, c-Cbl+/- mice exhibited higher perfusion, capillary density, endothelial permeability and beta catenin expression in the ligated limb compared to c-Cbl+/+ mice. Adenine diet significantly compromised all of these parameters in both c-Cbl+/- and c-Cbl+/+ mice. Mechanistic probing revealed that the uremic milieu inhibited Wnt activity and the nuclear pool of active beta catenin in the endothelial cells, which was in part driven by P-cresyl sulfate.
Conclusion
This study demonstrates the detrimental effect of uremia on ischemia induced angiogenesis and suppression of Wnt/beta catenin signaling in endothelial cells by specific uremic solutes. These results provide the first potential link of uremic solutes with a potent pro-angiogenic Wnt/beta catenin pathway. This interaction warrants further exploration as a potential CKD-specific mediator of PAD.
| Perfusion Index (Day 14) | Integrated density CD31 per micron surface area | Integrated density Dextran per micron surface area | ||||
| c-Cbl+/+ | c-Cbl+/- | c-Cbl+/+ | c-Cbl+/- | c-Cbl+/+ | c-Cbl+/- | |
| Normal Diet | 0.37 ±0.03 | 0.79 ±0.08 (p=0.01)* | 337.9±49.43 | 849.2±125.4(p=0.01)* | 87.44±9.71 | 147.9±24.97 (p=0.02) |
| 0.2% Adenine Diet | 0.26 + 0.07 (p = 0.05)# | 0.23 ± 0.20 | 92.40±14.17 (p<0.001)# | 117.6±10.46 | 51.81±4.99 (p=0.01)# | 66.84±5.63 |
*compares both groups on normal diet, #compares c-Cbl+/+ mice on adenine and normal chow
Funding
- NIDDK Support