transforming-growth-factor-beta and Aneurysm--Ruptured

Intracranial aneurysms (IA) are local dilatations in cerebral arteries that predominantly affect the circle of Willis. Occurring in approximately 2-5% of adults, these weakened areas are susceptible to rupture, leading to subarachnoid hemorrhage (SAH), a type of hemorrhagic stroke. Due to its early age of onset and poor prognosis, SAH accounts for > 25% of years lost for all stroke victims under the age of 65. In this review, we describe the cerebrovascular pathology associated with intracranial aneurysms. To understand IA genetics, we summarize syndromes with elevated incidence, genome-wide association studies (GWAS), whole exome studies on IA-affected families, and recent research that established definitive roles for Thsd1 (Thrombospondin Type 1 Domain Containing Protein 1) and Sox17 (SRY-box 17) in IA using genetically engineered mouse models. Lastly, we discuss the underlying molecular mechanisms of IA, including defects in vascular endothelial and smooth muscle cells caused by dysfunction in mechanotransduction, Thsd1/FAK (Focal Adhesion Kinase) signaling, and the Transforming Growth Factor β (TGF-β) pathway. As illustrated by THSD1 research, cell adhesion may play a significant role in IA.

Topics: Aneurysm, Ruptured; Animals; Arteritis; Case-Control Studies; Cerebral Arteries; Disease Models, Animal; Endothelial Cells; Exome Sequencing; Focal Adhesions; Genetic Predisposition to Disease; Genome-Wide Association Study; Hemorheology; Humans; Incidence; Intracranial Aneurysm; Mammals; Mechanotransduction, Cellular; Mice; Myocytes, Smooth Muscle; SOXF Transcription Factors; Subarachnoid Hemorrhage; Syndrome; Thrombospondins; Transforming Growth Factor beta; Zebrafish

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Aneurysm, Ruptured; Aortic Dissection; Celiprolol; Ehlers-Danlos Syndrome; Humans; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

The 19q13.3 locus for intracranial aneurysms (IA) partly overlaps with the 19q13 locus for abdominal aortic aneurysms (AAA). A common genetic risk factor located in this locus for the two aneurysm types seems plausible. The transforming growth factor beta (TGF-beta) signalling pathway plays a role in aortic aneurysms but may also play a role in aneurysms in general. In the combined region of the 19q13 loci for IA and AAA we identified two candidate genes that are both involved in the TGF-beta signalling pathway: hepsin (HPN) and the latent transforming growth factor beta-binding protein 4 (LTBP4). We hypothesised that single nucleotide polymorphisms (SNP) in the HPN and LTBP4 genes are associated with IA.. We analyzed all the common variations using tag SNP in the HPN and LTBP4 genes for association with IA in 390 patients and 642 controls in the Dutch population. Six tag SNP in the HPN gene and five tag SNP in the LTBP4 gene were genotyped.. No differences in SNP frequency were observed for both the HPN and LTBP4 gene between patients and controls.. Our findings suggest that variations in or near the HPN and LTBP4 genes do not play a role in the susceptibility to IA in the Dutch population.

Topics: Adult; Aged; Aged, 80 and over; Aneurysm, Ruptured; Aortic Aneurysm, Abdominal; Chromosome Mapping; Chromosomes, Human, Pair 19; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Humans; Intracranial Aneurysm; Latent TGF-beta Binding Proteins; Male; Middle Aged; Netherlands; Polymorphism, Single Nucleotide; Serine Endopeptidases; Signal Transduction; Subarachnoid Hemorrhage; Transforming Growth Factor beta