Fransen van der Putte, E. (Elies) (2012) The vascular smooth muscle endothelin B receptor; more than just a poor relation to the A receptor? thesis, Medicine.
Full text available on request.Abstract
Background and purpose: Endothelin-1 mediates its effects on blood pressure and vascular remodelling through receptor subtypes, located predominantly on various renal and vascular cells. Inhibition of endothelin A receptors, present on the vascular smooth muscle cells (VSMC), results in blood pressure reduction by loss of vascular tone and inhibition of patholophysiological neo-intima formation after vascular damage. Systemic endothelin B receptor (ETBR) deletion in genetically modified animals, results in: (1) Higher blood pressure, mainly due to loss of renal duct specific ETBRs; (2) increased circulating endothelin 1, mainly due to loss of vascular endothelial cell specific ETBRs, (3) increased pathophysiological vascular remodelling. The increase in blood pressure, and increased neo-intima formation cannot be fully explained by ETBR deletion in the renal duct or in vascular endothelial cells. Therefore the purpose of this study was to determine whether the ETBR, previously considered a “poor relation” to the endothelin A receptor, fulfils an essential role in the regulation of blood pressure and vascular remodelling. This was addressed using mice with VSMC-specific deletion of the ETBR in VSMC. Methods: VSMC ETBR deletion was generated in mice using a cre-lox combination and relevant animals were identified using PCR. Functional measurement of VSMC ETBR was achieved by measuring ETBR-mediated contraction in isolated tracheal rings supplemented by real time reverse transcription PCR, using RNA extracted from mouse aortas. Systolic blood pressure was measured using tail cuff plethysmography and ex vivo femoral artery reponses to endothelin 1 were measured to investigate the effect of VSMC ETBR deletion on vascular contractility. Vascular remodelling and angiogenesis in experimental animals were studied, using intra-luminal wire injury in the left femoral artery and ligation of the right femoral artery. Vascular remodelling was measured 32 days after injury using optical projection tomography and quantification. Angiogensis was measured in vivo using laser doppler perfusion imaging. Control animals used in in vivo experiments, were younger than knockdown animals, as age-matched controls were not available. Results: Significant VSMC ETBR knockdown, but not total deletion, was confirmed in experimental animals. Blood pressure in knockdown animals was reduced, without affecting femoral artery contratility. No differences were detected in neointimal remodelling or angiogenesis between knockdown animals and controls. Conclusion: These results suggest that reduced ETBR activity in smooth muscle cells results in reduced blood pressure, although this will need to be confirmed using apppropriate controls. As results from previous studies suggest up-regulation of VSMC ETBR in pathological conditions, the impact of VMSC ETBR deletion in models of hypertension would be of interest. Vascular remodelling results suggest no significant role for VSMC ETBRs in either neotimal lesion formation of angiogenesis.
| Item Type: | Thesis (Thesis) |
|---|---|
| Supervisor name: | Faculty supervisor: and Zeeuw, Prof. Dr. Dick de |
| Supervisor name: | External supervisors: and Webb, Prof. Dr. David and Hadoke, Dr. Patrick and The Queen’s Medical Research Institute and Centre for Cardiovascular Sciences and University of Edinburgh, Scotland |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Jun 2020 11:01 |
| Last Modified: | 25 Jun 2020 11:01 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/2090 |
Actions (login required)
 |
View Item |