Mammoto lab is interested in the role of angiogenesis in organ development, regeneration, aging and pathology. In particular, we focus on the following projects.
1. The role of angiogenesis in lung regeneration
Although epithelium is a major player in organ development and regeneration, blood vessels also play crucial roles in these processes. We are trying to understand the mechanism by which endothelial cells control lung development, regeneration and aging using multidisciplinary approaches. In particular, we focus on Wnt and the related signaling pathways (e.g. Twist1 and Yap1). To study the mechanism of angiogenesis in the lung, we have developed a unique method to implant hydrogel on the lung surface of a living mouse and successfully recapitulated lung-specific angiogenesis and various cellular interactions in the gel in both physiological and pathological conditions. Our long-term goal is to develop more effective endothelial-targeted strategies for lung regeneration.
Acceleration of Lung Regeneration by Platelet-Rich Plasma Extract through the Low-Density Lipoprotein Receptor-Related Protein 5-Tie2 Pathway. Am J Respir Cell Mol Biol 2016 Jan;54(1):103-13.
Endothelial YAP1 in Regenerative Lung Growth through the Angiopoietin-Tie2 Pathway. Am J Respir Cell Mol Biol. 2018 60(1): 117-1127.
Implantation of fibrin gel on mouse lung to study lung-specific angiogenesis. J Vis Exp 2014 Dec 21(94)
2. Mechanism of age-dependent decline in angiogenesis
Aging is associated with impaired angiogenesis, which contributes to the increased susceptibility to age-related lung diseases such as chronic lung diseases. We have reported that the Wnt ligand co-receptor, low-density lipoprotein receptor-related protein 5 (LRP5), mediates age-related inhibition of angiogenesis and alveolar morphogenesis. We are investigating further molecular mechanism by which aging inhibits lung vascular and alveolar morphogenesis using various transgenic animal models. In addition to soluble growth factors, biophysical factors such as changes in cell size, ECM stiffness, stretching forces, and flow control endothelial cell growth and differentiation. However, the mechanosensitive mechanism of age-dependent decline in angiogenesis and lung alveolar morphogenesis remains unclear. Thus, we also focus on the mechanosensitive mechanism of age-related decline in angiogenesis using various in vitro systems and transgenic animal models.
Effects of age dependent changes in cell size on endothelial cell proliferation and senescence through YAP1. Aging (Albany NY).
LRP5 in age-related changes in vascular and alveolar morphogenesis in the lung. Aging (Albany NY) 2019
3. Pulmonary hypertension
Pulmonary hypertension is a devastating pulmonary vascular disease characterized by aberrant muscularization of the normally non-muscularized distal pulmonary arterioles. We investigate the mechanism by which endothelial signaling controls vascular smooth muscle cell behaviors. The expression of the transcription factor, Twist1 is upregulated in the lungs of patients with pulmonary arterial hypertension (PAH), rats with type II bone morphogenetic protein receptor (BMPR2) gene mutation, a gene mutated in familial and idiopathic PAH, and chronic lung diseases accompanied with PH such as pulmonary fibrosis. We are studying the mechanism by which endothelial Twist1 and related genes control smooth muscle cell behaviors using in vitro assays, a hypoxia-induced experimental PH model, and transgenic animal models.
Twist1 in Hypoxia-induced Pulmonary Hypertension Through TGFβ-Smad Signaling. Am J Respir Cell Mol Biol. 2018 Feb; 58 (2): 194-207.
Team Mammoto at MCW