Elucidating the molecular mechanism of mechanotransduction in blood vessels and its application to vascular diseases
Blood vessels are constantly exposed to the mechanical stress caused by cyclic pumping of the heart.
However, 1) how vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) sense stress and convert to biochemical signals, 2) whether anatomically different vascular systems have distinct signaling pathway(s), and 3) how damaged/aged extracellular matrix of the vessels affects mechanotransduction, are largely unknown. We utilize mouse models of cardiovascular diseases and elucidate the molecular mechanism of mechanotransduction in the vessel wall by combining in vitrostretch assays, live imaging, and genome editing. We are currently collaborating with bioengineering, biomaterials, and clinical laboratories.(Sci Sig 2015, Circ Res 2018)
Generation of a mouse model with defective extracellular matrix and searching for a novel therapeutic strategy
Fibulin-4 is an extracellular matrix protein with tandem repeats of calcium binding EGF-like motifs abundantly expressed in the vessel wall. We generated a mouse model of ascending aortic aneurysms (SMKO) by deleting fibulin-4 specifically in vascular smooth muscle cells (SMCs) (Circ Res 2010). Temporal observations of the aortic wall of SMKO revealed a thickening of the medial layer and disruption of elastic fibers at 1 month of age. We found local upregulation of angiotensin converting enzyme and dedifferentiation of SMCs as well as an increase in pERK phosphorylation in the aneurysmal lesions. Blocking angiotensin-mediated signaling by ACE inhibitor or Angiotensin II receptor blocker was sufficient to prevent aneurysm formation (Sci Transl Med 2013); however, aneurysm growth was sustained in an angiotensin II independent manner once aneurysm was established. We are currently studying the intracellular signaling pathway(s) involved in each step of aneurysm growth and searching for new drug targets.
Collaborative Research with Aiko Sada Lab, IRCMS, Kumamoto University, Regulation of skin stem cells during development, homeostasis and aging
Our research interests focus on elucidating the basic properties and the regulatory mechanism of tissue stem cells by using mouse skin as a model system. We identified heterogeneous stem cell populations in the skin epidermis (Nature Cell Biology 2016) and established the genetic tools and molecular markers to analyze these cells in vivo. We are currently addressing how these stem cells are regulated during skin development, homeostasis, injury and aging. Our ultimate goal is to reveal the drivers and effectors of stem cell dysfunction. Targeting these factors may prevent or cure diseases at the stem cell level, with implications for future treatments for skin cancer, aging and other skin disorders.
Molecular mechanism of elastic fiber formation
Elastic fibers are abundantly distributed in the blood vessels, skin, lungs and vaginal wall and confer elasticity and recoiling to these tissues. We have shown that fibulin-5 binds to elastin, a core component of elastic fibers, lysyl oxidase like 1, an elastin-specific cross-linking enzyme, and microfibril, a scaffold for elastic fibers, and play an essential role in elastogenesis in vivo (Nature 2002, Nature Genetics 2004, Mol Cell Biol 2007). Mice deficient in the fibulin-5 gene exhibit loose skin and emphysematous lungs, and genetic mutations in the fibulin-5 gene were shown to be responsible for autosomal recessive cutis laxa type 1A (ARCL1A) in humans. Currently, we are searching for novel interacting proteins that affect elastic fiber formation or degeneration.
The mechanism by which ECM regulates extracellular environment
The vaginal wall of Fibulin-5 deficient mouse (center in B, KO) contains disrupted elastic fibers and the increased matrix metalloprotease-9 (MMP-9) activity mediated by fibronectin (FN)-integrin β1 binding, resulting in pelvic organ prolapse (Am J Pathol 2007, J Clin Invst 2011, PloS One 2013). When Mmp9 was deleted in KO mice, more than 60% of KO mice did not develop pelvic organ prolapse. When the integrin binding domain of fibulin-5 was disrupted in vivo (right in B, RGE), elastic fibers were normal although the MMP-9 activity was increased. When RGE mice were treated with BAPN, an inhibitor of lysyl oxidase, preclinical pelvic organ prolapse was observed. We are currently searching for novel protease(s) involved in degradation of elastic fibers.