(Toronto, ON – May 24, 2011) In a pivotal study, Mount Sinai Hospital researchers including Drs. Susan Quaggin and Marie Jeansson, as well as colleagues in Toronto, Germany and Austria, have uncovered a new role for the growth factor angiopoietin-1 (Angpt1)—a discovery that may lead to the development of new strategies to improve therapies for diabetes, cancer and malaria.
The findings were reported online yesterday in the Journal of Clinical Investigation.
“Our study shows, for the first time, a key role for the angiopoietin protein in protecting the vasculature system in diseases such as diabetes,” said Dr. Susan Quaggin, Senior Investigator at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital, a physician at St. Michael’s Hospital and a Professor at the University of Toronto.
Scientists had known that certain illnesses including diabetes are characterized by pathologic angiogenesis (i.e., damaged blood vessels), as well as altered levels of proteins called angiopoietins. Such vascular damage can lead to severe and life-threatening complications including diabetic nephropathy, the leading cause of kidney disease in North America. But no research to date had determined if there is a functional role for these proteins in the development and progression of illness.
“Our research is the first to show that Angpt1 protects the vascular system against scarring, or fibrosis, and safeguards against tissue injury and microvascular disease in diabetes, for example,” said first author and Lunenfeld post-doctoral trainee Dr. Marie Jeansson. “Angpt1 functions like the brakes in a car—required to stop a moving vehicle but redundant in a stationary one.”
The researchers used genetically engineered mice that had the Angpt1 gene ablated at various time points during development from conception to adulthood, so that they could study what happened in the absence of Angpt1 and learn more about the signaling pathway.
Results showed that Angpt1 is critical for blood vessel growth and development of the heart during fetal development, but is essentially irrelevant during adulthood. The protein only exerts its protective effects over the vascular system once an illness that causes vascular ‘stress,’ such as diabetes, develops. In the absence of Angpt1 and in the case of diabetes, for example, the uncontrolled blood vessel growth and scarring of the vascular system can lead to kidney damage and failure.
Dr. Quaggin noted that understanding the role of Angpt1 and related proteins may help clinicians develop more effective means for earlier detection and patient risk stratification, as well as more effective therapies. “Manipulating the Angpt1 pathway may have less systemic side effects and may be more tolerable for patients than other anti-angiogenic agents that target factors such as VEGF, which appears to be more essential in healthy blood vessels.”
Dr. Quaggin believes that the findings can also be applied to develop more effective biomarkers and potential therapies for cancer and malaria—both illnesses characterized by alterations in the vasculature.
The study was supported by the Canadian Institutes of Health Research as well as the Terry Fox Research Institute.
Some of the limitations of current anti-angiogenic medications lie in their non-specific actions on healthy cells as well as tumour vasculature. These actions may lead to side effects including kidney damage, hypertension, ulcers, severe headaches and stroke. Dr. Quaggin and her team are identifying ways to develop new therapies that selectively suppress blood vessel formation in diseases such as diabetes, without damaging health tissues.