Malfunction and malformation of blood vessels are associated with a broad range of medical conditions, including cancer, cardiovascular diseases, and neurological disorders. The ultimate goal of Dr. Komatsu’s research is to find a way to reverse the process of abnormal vessel formation and remodeling, and restore normal function to these vessels. Normalization of blood vessels provides unique therapeutic opportunities. It can enhance the efficacy of cancer treatments, reestablish blood flow to ischemic hearts and limbs, avoid vascular complications in diabetes, and prevent blindness caused by damaging of the retina in diabetic and elderly people. Newly formed blood vessels must undergo a maturation process. The defects in this process result in the formation of functionally defective blood vessels, which is typically seen in pathological lesions. Dr. Komatsu’s research is uncovering key molecular pathways that promote the vessel maturation process.
Blood vessel formation and maturation are regulated by the balance between pro-angiogenic and antiangiogenic signals. Dr. Komatsu’s group has identified a key role for the small GTPase R-Ras in promoting vessel maturation while attenuating excessive angiogenic response in pathologically regenerating vasculature. R-Ras is highly expressed in fully differentiated, quiescent vascular smooth muscle cells, endothelial cells, and pericytes of the mature adult vasculature. Unlike prototypic oncoprotein Ras such as K-Ras, R-Ras inhibits vascular cell proliferation and invasion and promotes vascular quiescence. R-Ras signaling primarily affects vessel remodeling and regeneration by counterbalancing vessel activation. The elevated R-Ras expression normalizes pathologically regenerating vasculature.
Regulation of blood vessels by R-Ras
There is currently no successful strategy for promoting vascular maturation for therapeutic purposes. The studies conducted by Dr. Komatsu’s group showed that R-Ras coordinates multiple signaling events in endothelial cells and pericytes to redirect nascent vessel formation from angiogenic sprouting to vessel stabilization. The group also showed an important activity of R-Ras to facilitate tubulogenesis (creation of lumen) of growing vessels via non-canonical Akt pathway that stabilizes microtubule cytoskeleton. The unique multifaceted activities of R-Ras make the R-Ras pathways an important subject of the investigation to search for a new strategy for manipulating blood vessel function.
Innovation in drug delivery technology
The other area of Dr. Komatsu’s research is to develop novel vascular targeting strategies for delivery of therapeutics in various human diseases. Vascular targeting technology takes advantage of unique molecular signatures of blood vessels at specific sites in the body. This technology enables direct delivery of drugs to tumors and other diseased tissues through the vascular network. Since drugs are targeted to specific sites, it is possible to enhance the drug efficacy while substantially reducing unwanted side-effects of the drugs.
Dr. Komatsu’s group succeeded in targeting the lung lesions of pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary vascular resistance. PAH is a serious lung disorder, which can lead to right heart failure and death. There is currently no effective treatment for PAH. Dr. Komatsu’s group used a 9 amino-acid cyclic peptide, CARSKNKDC (CAR) to selectively target PAH lesions. The unique property of the CAR peptide offers a novel drug delivery system for PAH.
Technology Expertise Keywords
Development of vascular targeting technology for organ/lesion-specific drug delivery; Development of vascular imaging technology
Perrot C, Sawada J, and Komatsu M. Prolonged activation of cyclic AMP signaling leads to endothelial barrier disruption via transcriptional repression of RRAS. FASEB journal. 2018; 32(11): 5793-5812. PMID: 29775418
Li F, Sawada J, and Komatsu M. R-Ras-Akt axis induces endothelial lumenogenesis and regulates the patency of regenerating vasculature. Nature Communications. 2017; 8(1):1720, PMID: 29170374
Sawada J, Urakami T, Li F, Urakami A, Zhu W, Fukuda M, Li DY, Ruoslahti E, Komatsu M. Small GTPase R-Ras regulates integrity and functionality of tumor blood vessels. Cancer Cell. 2012 Aug 14;22(2):235-49. doi: 10.1016/j.ccr.2012.06.013. PMID: 22897853
Urakami T, Järvinen TA, Toba M, Sawada J, Ambalavanan N, Mann D, McMurtry I, Oka M, Ruoslahti E, Komatsu M. Peptide-directed highly selective targeting of pulmonary arterial hypertension. Am J Pathol. 2011 Jun;178(6):2489-95. doi: 10.1016/j.ajpath.2011.02.032. PMID: 21549345
Komatsu M, Ruoslahti E. R-Ras is a global regulator of vascular regeneration that suppresses intimal hyperplasia and tumor angiogenesis. Nature Medicine 2005 Dec;11(12):1346-50. PMID: 16286923
R-Ras activity in vascular regulation
Patent # U.S. Patent No. US8506965 B2
CAR Peptide for Homing, Diagnosis & Targeted Therapy for Pulmonary and Fibrotic Disorders
Patent # U.S. Patent No. US9180161 B2