Collagen type IV in vascular biology
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Cardiovascular Science
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Collagen type IV is the major structural component of the basement membrane, a specialised extracellular matrix structure. In blood vessel walls, this membrane surrounds smooth muscle cells and separates them from endothelial cells. Recently, we have characterised an allelic series of Col4a1 (type IV collagen alpha chain 1) mouse mutants with eye and kidney phenotypes of varying severity. Basement membrane defects in aortae of one of these mutants lead to focal separation of endothelial from smooth muscle cells. A novel role for Col4a1 was identified by functional analysis of aortic endothelial and smooth muscle cells which showed alterations in nitric oxide (NO)-mediated vasodilation due to increased nitric oxide sensitivity. Surprisingly, blood pressure analysis revealed that these animals were hypotensive.
Aims of the project
1. Investigation of the molecular consequences of Col4a1 mutations and elucidation of the genotype-phenotype correlation.
Col4a1 secretion will be analysed to determine whether mutant proteins accumulate in the cell and/or are incorporated in the basement membrane. The consequences of mutant protein retention on cell biology and defective protein incorporation into the basement membrane will be addressed as appropriate. The contribution of these events to the phenotype of Col4a1 mutant animals will be tested.
2. Analysis of the vascular phenotypes of Col4a1 mutants.
The effects of col4a1 mutations on NO-dependent and NO-independent vasodilation pathways will be analysed in conduit and resistance vessels. The cause of altered NO sensitivity and mechanism of adaptation in smooth muscle cells will be determined.
3. Characterisation of the hypotension.
The hypotension will be analysed to determine whether it is age related, mutation specific and associated with the observed vasodilation abnormalities.
A combination of mouse genetics, myography, cell culture and molecular biology will be employed to investigate these aims and a collaboration will examine vasodilation in human families with COL4A1 mutations.
In conclusion, this research will provide insight into the mechanism by which Col4a1 mutations affect cell and basement membrane function, the genotype-phenotype correlation of Col4a1 mutants and the role of collagen type IV in vascular tone maintenance. This may identify a general mechanism employed by the vasculature to adapt to altered NO levels and form a paradigm for the role of other basement membrane proteins in vascular biology. Consequently this work will increase our understanding of the pathways and mechanisms of vascular disease.
Aims of the project
1. Investigation of the molecular consequences of Col4a1 mutations and elucidation of the genotype-phenotype correlation.
Col4a1 secretion will be analysed to determine whether mutant proteins accumulate in the cell and/or are incorporated in the basement membrane. The consequences of mutant protein retention on cell biology and defective protein incorporation into the basement membrane will be addressed as appropriate. The contribution of these events to the phenotype of Col4a1 mutant animals will be tested.
2. Analysis of the vascular phenotypes of Col4a1 mutants.
The effects of col4a1 mutations on NO-dependent and NO-independent vasodilation pathways will be analysed in conduit and resistance vessels. The cause of altered NO sensitivity and mechanism of adaptation in smooth muscle cells will be determined.
3. Characterisation of the hypotension.
The hypotension will be analysed to determine whether it is age related, mutation specific and associated with the observed vasodilation abnormalities.
A combination of mouse genetics, myography, cell culture and molecular biology will be employed to investigate these aims and a collaboration will examine vasodilation in human families with COL4A1 mutations.
In conclusion, this research will provide insight into the mechanism by which Col4a1 mutations affect cell and basement membrane function, the genotype-phenotype correlation of Col4a1 mutants and the role of collagen type IV in vascular tone maintenance. This may identify a general mechanism employed by the vasculature to adapt to altered NO levels and form a paradigm for the role of other basement membrane proteins in vascular biology. Consequently this work will increase our understanding of the pathways and mechanisms of vascular disease.
Organisations
People |
ORCID iD |
| Tom Van Agtmael (Principal Investigator) |