Blockade of TGF-β (Transforming Growth Factor Beta) Signaling by Deletion of Tgfbr2 in Smooth Muscle Cells of 11-Month-Old Mice Alters Aortic Structure and Causes Vasomotor Dysfunction
This week we profile a recent publication in Arteriosclerosis, Thrombosis, and Vascular Biology from Dr. Chloe Lee (pictured, left) and the laboratory of Dr. David Dichek (right) at UW.
Can you provide a brief overview of your lab’s current research focus?
Our lab is focused on understanding the molecular mechanisms that cause vascular disease and on developing novel molecular therapies. We work primarily with animal models of vascular disease (mice and rabbits), but some of our work extends to human vascular tissues. We develop gene-based therapies that prevent and reverse atherosclerosis by stimulating cholesterol transport out of the blood vessel wall. We also aim to understand the mechanisms through which abnormal transforming growth factor beta (TGF-β) signaling contributes to aortic aneurysms.
What is the significance of the findings in this publication?
Excessive TGF-β signaling in smooth muscle cells is implicated as a cause of aortic aneurysms in Marfan syndrome and other clinical settings. Accordingly, antagonism of TGF-β signaling was proposed as a treatment for aortic aneurysms. However, our laboratory and others showed that TGF-β signaling in smooth muscle cells during embryogenesis and early postnatal life is essential for normal aortic development. This observation left open the possibility that antagonism of TGF-β signaling in adult life might not be harmful. To address this question, we used a genetic approach to ablate TGF-β signaling in smooth muscle cells of adult (11-month-old) mice. Ablation of smooth muscle cell TGF-β signaling caused structural and functional abnormalities of the proximal aorta. Although these abnormalities are less severe than those in young mice, they suggest a cautious approach to the development of treatments that antagonize TGF-β signaling in adults.
What are the next steps for this research?
We are extending the time course of the study, to determine whether ablation of smooth muscle cell TGF-β signaling in older mice leads to aneurysm formation (as it does in young mice). We are also now working with a mouse model of aneurysmal disease that is caused by a loss-of-function mutation in the type 2 TGF-β receptor. This mutation causes Loeys-Dietz syndrome in humans. We aim to understand the pathogenesis of aortic disease and to develop new treatments.
If you’d like us to mention your funding sources, please list them.
Our work on aneurysms is funded by the National Heart Lung and Blood Institute and the John L. Locke, Jr. Charitable Trust.