The aorta is the largest artery in our bodies. It starts in the left ventricle of the heart and extends until the abdomen, emitting multiple branches that irrigate all organs in our body. At each contraction, the heart ejects blood into the aorta and the wall of this vessel has a series of specializations that allow it to manage periodic bursts of blood at high pressure. In comparison with smaller blood vessels, the aortic wall is rich in vascular smooth muscle cells. Due to the elastic and contractile properties conferred by smooth muscle cells, the aorta has the capacity to dilate to receive incoming blood when the heart contracts. When the hearts relaxes to refill with more blood, the aorta returns to its normal diameter, pushing blood at a constant flow to the downstream vasculature network. Importantly, in certain pathological situations caused by genetic predisposition or by risk factors such as smoking, the wall of the aorta loses its elasticity/contractility and starts ballooning, forming a lesion named aneurysm. Once detected, aneurysms can be treated by open surgical repair or endovascular approaches with excellent survival rates (95% 30-day survival). However, these lesions frequently develop completely asymptomatic and are only detected when it is too late for clinical action, i.e. after rupture or dissection. Ruptured aneurysms represent a very relevant socio-economical burden, accounting for 1 to 2% of all deaths in developed countries. To prevent these fatalities, it is imperative to develop strategies for early identification of individuals at risk. Thanks to efforts from multiple clinicians and laboratories, disease-causing mutations have been identified in 23% of familial aneurysmal cases. All these mutations affect genes encoding proteins necessary for proper function of smooth muscle cells: extracellular matrix proteins, membrane receptors and contractile proteins. Notably, regardless all progress achieved, disease-causing mutations still need to be found for a large majority of cases.
Transcription factors are a type of protein that regulates what genes get activated and repressed in each cell. Due to this function, transcription factors sit at the top of complex genetic hierarchies regulating the properties and function of distinct cell types, including those that compose the artic wall. Notably, even though we know a number of transcription factors acting in vascular smooth muscle, little is known as to vascular smooth muscle transcription factors involved in preventing or promoting aneurysmal formation. Our preliminary research using transgenic mouse models showed that the transcription factor TBX18 is selectively expressed by vascular smooth muscle and that absence of TBX18 leads to development of aortic lesions that resemble human aneurysms. The aims of this project are: i) to perform a time course analysis of the pathogenic events leading to development of aortic aneurysms in Tbx18-mutant mice; ii) to determine what genes are regulated by TBX18 in vascular smooth muscle, with emphasis on known disease-causing genes; iii) to look for mutations in Tbx18 in human patients with aneurysmal diseases.
