Etv5-Mediated Elastic Fiber Generation in Chronic Aortic Dissection

ABSTRACT Aortic dissection (AD) is a life-threatening vascular disease characterized by a tear of the aortic wall. ADs restricted to the descending aorta are typically managed conservatively in the acute phase, but many patients require surgical repair due to aortic dilatations and/or impending rupture in the chronic phase. No medication has been approved for lessening the progression of ADs, highlighting a need for its mechanistic understanding. Elastic fibers are an important component of the aortic wall that provides structural stability and elasticity. However, it remains unknown how elastic fibers are regulated in ADs. In my preliminary studies using a mouse model of ADs, we found that elastic fibers were newly synthesized in the vascular wall of chronic ADs in survived mice accompanied by enhanced transcription of aortic elastin mRNA. Immunostaining demonstrated that the vascular wall of the false lumen was composed of smooth muscle cells (SMCs) and de novo elastic fibers were distributed close to SMCs. These data indicate that SMCs are the major cell type generating elastic fibers in dissected aortas. Unbiased transcriptomic analysis identified Etv5 as a potential molecule regulating elastin transcription. Transcription factor alignment analysis predicted that Etv5 binds to both promoter and enhancer regions of elastin DNA. Notably, histological analyses showed that Etv5 was spatially coincident with elastin mRNA, de novo elastic fibers, and SMCs. These results suggest the contribution of Etv5 in SMCs to elastic fiber synthesis in the chronic phase of ADs. Given the important role of elastic fibers in the physiological condition, de novo elastic fibers would compensate structural vulnerability of the vascular wall in ADs. Here, I hypothesize that Etv5 regulates the generation of de novo elastic fibers in SMCs, thereby strengthening the vascular wall of chronic ADs. This central hypothesis will be tested with the following two specific aims. Aim 1: Determine whether Etv5 mediates de novo elastic fiber generation following ADs. Aim 2: Determine the impact of de novo elastic fibers on aortic complications in chronic ADs. This proposed project will provide new insights into understanding the mechanisms by which de novo elastic fiber generation is regulated during AD progression. ABSTRACT FOR LAYPERSONS A tear of the largest blood vessel in the body is a severe condition known as aortic dissection. Some patients can be managed without surgery in the early stage. But many of them need surgical treatment eventually due to the risk of death resulting from disease progression. Sadly, there are no drugs to slow down the progression of the disease. This highlights a need to understand how the disease progresses. To develop effective drugs for the disease, my project will investigate mechanisms regarding disease progression. I will particularly focus on elastic fibers, a key structure of the vessel wall. Elastic fiber gives strength to the vessel. However, it has not been fully understood how this fiber acts in aortic dissection. In my preliminary studies using mice, I explored how elastic fibers behave in aortic dissection, especially in the late stage. I discovered that elastic fibers were newly made in disease vessels. I also noticed that there was an increase in gene copies for elastin, a component of elastic fibers. A gene screening examination identified Etv5 as a potential regulator of elastin expression. Of interest, this molecule was found in the same places as the newly-formed elastic fibers. This led us to think that Etv5 may be involved in the formation of new elastic fibers in the late stage of aortic dissection. Based on these findings, I expect that Etv5 leads to new elastic fiber formation, making the aortic wall stronger in aortic dissection. To test this expectation, I will investigate two questions. (1) I will investigate if Etv5 regulates elastin gene expression and elastic fiber formation in aortic dissection. (2) I will investigate the role of new elastic fibers in aortic dissection This research project will reveal how the body attempts to repair and strengthen the aortic wall during the progression of aortic dissection. Understanding these mechanisms could lead to the development of new treatment options that target new elastic fiber formation in patients with aortic dissection.