[Apr. 15, 2023: Staff Writer, The Brighter Side of News]
Every year, more than 15 million people suffer a stroke, and more than six million people die from the condition. (CREDIT: Creative Commons)
According to the World Health Organization, stroke is the second leading cause of death and the third leading cause of disability worldwide. Every year, more than 15 million people suffer a stroke, and more than six million people die from the condition. In the United States alone, stroke is responsible for more than 140,000 deaths each year.
A study led by Weill Cornell Medicine scientists has found that strokes cause significant changes in gene activity in small blood vessels in the brain, and these changes could be targeted with existing or future drugs to mitigate brain injury or improve stroke recovery. The study, which was published in the Proceedings of the National Academy of Sciences catalogued hundreds of genes with significant stroke-driven changes that have likely relevance in human strokes.
The researchers performed a comprehensive survey in a preclinical model of gene activity changes in small blood vessels in the brain following stroke. Comparing these changes to those that have been recorded in stroke patients, they found 541 genes whose activity was altered similarly in both mice and human cerebral microvessels post-stroke.
“Our findings provide a knowledge base that improves our understanding of strokes and points to specific molecules and pathways that can now be investigated as potential targets for future stroke treatments,” said study senior author Dr. Teresa Sanchez, assistant professor of pathology and laboratory medicine and principal investigator of the Laboratory of Molecular and Translational Vascular Research at Weill Cornell Medicine.
Stroke is a leading cause of mortality and long-term disability worldwide, and the vast majority of strokes are ischemic strokes involving a blood clot in a vessel serving the brain. The blockage or severe reduction of blood flow reduces oxygen and nutrient delivery to downstream brain cells, killing or injuring them and triggering inflammatory processes that can cause further damage. The small cerebral blood vessels—or “cerebral microvasculature”—downstream of the blockage are also affected, and the changes in them are thought to contribute further to brain damage post-stroke.
However, these microvascular changes have been technically challenging to record accurately, and thus have not been as well studied as other aspects of stroke—nor do they have any specific treatment.
In the new study, Dr. Sanchez and her team used the latest optimized methods, recently published by the Sanchez laboratory in Nature Protocols, for studying stroke-affected vessels to surmount these challenges. They comprehensively recorded post-stroke changes in gene activity in the cerebral microvasculature in mice and identified the changes that have also been seen in studies of human stroke patients.
In the inset, the small blood vessels in the brain, i.e. the cerebral microvasculature, can be seen at a higher magnification stained in red and the molecules that weaken the blood brain barrier are labeled in white. (CREDIT: PNAS)
The team identified several major clusters of genes with altered activity based on their functional roles and disease links. These included clusters relating to general inflammation, brain inflammation, vascular disease, and the type of vascular dysfunction that would cause cerebral microvessels to become leaky. This leakiness implies a weakening of the “blood-brain barrier,” the cellular lining of cerebral microvessels that protects the brain by keeping most components of circulating blood out of it.
“We found that, following stroke, some molecules that would weaken the blood-brain barrier were upregulated, while others that should protect the blood-brain barrier were downregulated,” said Dr. Sanchez, who is also an assistant professor of neuroscience in the Feil Family Brain and Mind Research Institute. “This is consistent with clinical observations of blood-brain-barrier disruptions following stroke.”
Stroke-induced cerebral microvascular dysfunction contributes to aggravation of neuronal injury and compromises the efficacy of current reperfusion therapies. (CREDIT: PNAS)
The analysis also identified the disruption of normal activity in genes controlling the levels of sphingolipids. These fat-related molecules are heavily involved in regulating blood vessels, and disruptions of their normal workings have been observed in stroke, atherosclerosis and vascular dementia.
The team discovered that some types of these sphingolipids are highly enriched in cerebral blood vessels compared with brain tissue. In addition, they identified alterations in these sphingolipids in the cerebral microvasculature induced by stroke as well as the changes in key molecules that control the levels of these lipids. These new findings will permit the pharmacological targeting of these pathways for stroke therapeutic discovery.
The study included assessments confirming the “druggability,” or suitability for targeting with small-molecule drugs, of many of the molecules with altered production post-stroke. Indeed, some of the identified molecules are already being targeted by candidate drugs to treat other pathological conditions, which could facilitate the repurposing of these drugs for the treatment of stroke and dementia.
Dr. Sanchez and her team are now following up with preclinical experiments using candidate drugs or genetic methods to reverse some of the specific microvascular changes identified in their study, to investigate if this could be beneficial for stroke patients.
“We’ve generated this knowledge platform and we’re using it, but we also hope that other scientists will join us in these efforts to develop the first therapies targeting the microvasculature in stroke,” she said.
The potential for new treatments is welcome news in the field of stroke research, as current treatments for the condition are limited. One of the few treatments available, tissue plasminogen activator (tPA), can only be used within a few hours of the onset of a stroke, and only for certain types of strokes. Additionally, tPA can increase the risk of bleeding in the brain and is not suitable for all patients.
Dr. Sanchez’s study offers new hope for stroke patients and their families, as it identifies specific molecules and pathways that can be targeted with drugs to mitigate brain injury or improve stroke recovery. The study’s findings could also have implications for the treatment of other neurological conditions, such as dementia, which is often associated with vascular disease.
Dr. Sanchez’s study was supported by the National Institutes of Health, the American Heart Association, the New York State Department of Health and Weill Cornell Medicine’s Clinical and Translational Science Center.
The study’s co-first author, Dr. Keri Callegari, a postdoctoral associate in the Laboratory of Molecular and Translational Vascular Research at Weill Cornell Medicine, said the study’s findings have the potential to revolutionize the treatment of stroke and other neurological conditions.
“This study offers new insights into the complex molecular changes that occur in the microvasculature following stroke,” Dr. Callegari said. “Our findings provide a roadmap for the development of new therapies that could improve stroke recovery and reduce the risk of neurological complications, such as dementia.”
The study’s co-first author, Dr. Sabyasachi Dash, a postdoctoral associate in the Laboratory of Molecular and Translational Vascular Research at Weill Cornell Medicine, said the study’s findings could lead to the development of new drugs that target the microvasculature in stroke patients.
“Our study has identified specific molecules and pathways that can be targeted with drugs to mitigate brain injury or improve stroke recovery,” Dr. Dash said. “This is a major step forward in the development of new treatments for stroke and other neurological conditions.”
Dr. Sanchez and her team are now planning to expand their study to include human patients, to confirm that the findings in their preclinical model are applicable to human stroke. If successful, the team hopes to develop clinical trials to test the safety and efficacy of drugs targeting the microvasculature in stroke patients.
The potential for new treatments is welcome news for stroke patients and their families, who often face long-term disability and reduced quality of life after a stroke. With further research and development, the findings of Dr. Sanchez’s study could offer hope for a brighter future for stroke patients around the world.
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