Abstract
BackgroundCirculating agonistic autoantibodies acting at G protein-coupled receptors have been associated with numerous sever pathologies in humans. Antibodies directed predominantly against the α1-adrenergig receptor were detected in patients suffering from widespread diseases such as hypertension and type 2 diabetes. Their deleterious action has been demonstrated for peripheral organs. We postulate that antibodies to the α1-adrenergig receptor are relevant pathomolecules in diseases of the central nervous system associated with vascular impairments.Methodology/Principal FindingsUsing a rat model we studied the long-term action of antibodies against the α1-adrenergig receptor either induced by immunization with a receptor peptide or applied by intravenous injection. The vasculature in the rat brains was investigated by time-of-flight magnetic resonance angiography using a 9.4 Tesla small animal MR imaging system. Visual examination of maximum-intensity-projections (MIPs) of brain angiographs revealed the development of vascular defects in antibody- exposed animals between three and eight months of treatment. Relative vascular areas were derived from representative MIP image sections by grayscale analysis and used to form an index of vascular circulation. Animals exposed to the action of α1-adrenergig receptor antibodies showed significantly reduced vascular areas (p<0.05). Calculated index values indicated attenuated blood flow in both antibody-treated cohorts compared to their respective controls reaching with (relative units ± standard error, n = 10) 0.839±0.026 versus 0.919±0.026 statistical significance (p<0.05) for peptide-immunized rats.Conclusion/SignificanceWe present evidence that antibodies to the α1-adrenergig receptor cause cerebrovascular impairments in the rat. Our findings suggest the pathological significance of these antibodies in pathologies of the human central nervous system linked to impairments of brain vasculature such as stroke and dementia.
Highlights
Structural and functional impairments of the vasculature are causally linked or significantly contribute to different pathologies in humans, among them numerous widespread diseases
Our findings suggest the pathological significance of these antibodies in pathologies of the human central nervous system linked to impairments of brain vasculature such as stroke and dementia
The peptide used for immunizing rats corresponds to the cell surface epitope of the rat a1-adrenergic receptor (a1-AR) which is permanently exposed to the immune system
Summary
Structural and functional impairments of the vasculature are causally linked or significantly contribute to different pathologies in humans, among them numerous widespread diseases. Brain vasculature is critical for the development of different types of dementia such as Alzheimer’s and vascular dementia. Circulating agonistic autoantibodies acting at G protein-coupled receptors have been associated with numerous sever pathologies in humans. Antibodies directed predominantly against the a1-adrenergig receptor were detected in patients suffering from widespread diseases such as hypertension and type 2 diabetes. Their deleterious action has been demonstrated for peripheral organs. We postulate that antibodies to the a1-adrenergig receptor are relevant pathomolecules in diseases of the central nervous system associated with vascular impairments
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