A fresh study discovers a novel reason for brain hemorrhages, not just blood vessel injury

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BY AARON ROTTENBERG, List23

The discovery that cerebral microbleeds can be caused by mature red blood cells interacting with brain capillaries is the result of recent research, which contradicts the belief that these bleeding events occur solely due to blood vessel damage.

A new finding from the University of California, Irvine has revealed that cerebral microbleeds can be caused by a combination of older red blood cells and brain capillaries.

The discovery contributes to a better understanding of the mechanisms behind these bleeding, which can lead to the development of new therapeutic interventions to manage and prevent these conditions.

Recent research published in the Journal of Neuroinflammation reveals that the team observed how red blood cells stall in brain capillaries and analyzed the process of hemorrhage.

Dr. Mark Fisher, a neurology professor at UCI’s School of Medicine, emphasized the importance of this study in extending our understanding of the mechanism behind cerebral microbleeds.

After tert-butyl hydroperoxide was exposed to them, the team used a fluorescent label to mark the cells and inject them into mice. They observed that the red blood cells became trapped in the brain capillaries and then cleared out in endothelial erythrophagocytosis, leading to hemorrhage in the brain as microglia engulfed the cells as they moved out of the capillaries.

It has long been thought that blood vessels must be injured or disrupted to cause cerebral hemorrhage, but additional research suggests that increased red blood cell interactions with brain capillaries offer a unique means of development.

The findings, published in the democratic college in New York on October 18, 2017, suggest that learning or movement through connections between retinal and cynical nerves may result in milder symptoms, which could indicate cancer progression.

Rachita Sumbria, Hai Zhang, Rudy Chang, Jiahong Sun, David Cribbs, and Todd Holmes worked together to maximize the benefits of the Center for Neural Circuit Mapping’s comprehensive infrastructure and robust resources.

The National Institute on Aging and the National Institute of Neurological Disorders and Stroke donated their support for this work.

Click here to read full List23 article.

TEAM FINDS NEW CULPRIT BEHIND BRAIN HEMORRHAGE FORMATION

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Photo: “Our current study is significant in expanding our understanding of the mechanism by which cerebral microbleeds develop,” says  Mark Fisher. “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.” (Credit: Lisa Yount/Unsplash)

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A first-of-its-kind study has revealed a new culprit in the formation of brain hemorrhages that does not involve injury to the blood vessels, as previously believed.

Researchers discovered that interactions between aged red blood cells and brain capillaries can lead to cerebral microbleeds, offering deeper insights into how they occur and identifying potential new therapeutic targets for treatment and prevention.

The findings, published in the Journal of Neuroinflammation, describe how the researchers were able to watch the process by which red blood cells stall in the brain capillaries and then observe how the hemorrhage happens.

Cerebral microbleeds are associated with a variety of conditions that occur at higher rates in older adults, including hypertension, Alzheimer’s disease, and ischemic stroke.

“We have previously explored this issue in cell culture systems, but our current study is significant in expanding our understanding of the mechanism by which cerebral microbleeds develop,” says co-corresponding author Mark Fisher, professor of neurology in the University of California, Irvine School of Medicine. “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.”

The team exposed red blood cells to a chemical called tert-butyl hydroperoxide that caused oxidative stress; the cells were then marked with a fluorescent label and injected into mice.

Using two different methods, the researchers observed the red blood cells getting stuck in the brain capillaries and then being cleared out in a process called endothelial erythrophagocytosis. As they moved out of the capillaries, microglia inflammatory cells engulfed the red blood cells, which led to the formation of a brain hemorrhage.

“It has always been assumed that in order for cerebral hemorrhage to occur, blood vessels need to be injured or disrupted. We found that increased red blood cell interactions with the brain capillaries represent an alternative source of development,” says co-corresponding author Xiangmin Xu, professor of anatomy and neurobiology and director of the campus’s Center for Neural Circuit Mapping.

“We need to examine in detail the regulation of brain capillary clearance and also analyze how that process may be related to insufficient blood supply and ischemic stroke, which is the most common form of stroke, to help advance the development of targeted treatments.”

The National Institute on Aging and the National Institute of Neurological Disorders and Stroke funded the work.

Source: UC Irvine

Revolutionary Study Unveils New Cause of Brain Hemorrhages Beyond Blood Vessel Injury

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Photo: New research has revealed that aged red blood cells interacting with brain capillaries can cause cerebral microbleeds, a finding that upends the traditional belief that these hemorrhages only result from blood vessel injury. This breakthrough offers new avenues for understanding and treating conditions related to aging and brain health.

By UNIVERSITY OF CALIFORNIA, IRVINE

The discovery improves our understanding of cerebral microbleeds and may offer new therapeutic targets.

A groundbreaking study conducted by the University of California, Irvine has uncovered a novel factor contributing to the development of brain hemorrhages. Contrary to previous assumptions that linked hemorrhages solely to blood vessel injury, this research found that the interplay between older red blood cells and brain capillaries can cause cerebral microbleeds.

This discovery provides a deeper understanding of the mechanisms behind these bleeds and opens up new avenues for therapeutic interventions aimed at treating and preventing them.

Study Methodology and Observations

The findings, recently published in the Journal of Neuroinflammation, describe how the team was able to watch the process by which red blood cells stall in the brain capillaries and then observe how the hemorrhage happens. Cerebral microbleeds are associated with a variety of conditions that occur at higher rates in older adults, including hypertension, Alzheimer’s disease, and ischemic stroke.

“We have previously explored this issue in cell culture systems, but our current study is significant in expanding our understanding of the mechanism by which cerebral microbleeds develop,” said co-corresponding author Dr. Mark Fisher, professor of neurology in UCI’s School of Medicine. “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.”

Mechanism Behind Brain Hemorrhages

The team exposed red blood cells to a chemical called tert-butyl hydroperoxide that caused oxidative stress; the cells were then marked with a fluorescent label and injected into mice. Using two different methods, the researchers observed the red blood cells getting stuck in the brain capillaries and then being cleared out in a process called endothelial erythrophagocytosis. As they moved out of the capillaries, microglia inflammatory cells engulfed the red blood cells, which led to the formation of a brain hemorrhage.

Implications and Future Research Directions

“It has always been assumed that in order for cerebral hemorrhage to occur, blood vessels need to be injured or disrupted. We found that increased red blood cell interactions with the brain capillaries represent an alternative source of development,” said co-corresponding author Xiangmin Xu, UCI professor of anatomy & neurobiology and director of the campus’s Center for Neural Circuit Mapping. “We need to examine in detail the regulation of brain capillary clearance and also analyze how that process may be related to insufficient blood supply and ischemic stroke, which is the most common form of stroke, to help advance the development of targeted treatments.”

Reference: “Erythrocyte–brain endothelial interactions induce microglial responses and cerebral microhemorrhages in vivo” by Hai Zhang, Rachita K. Sumbria, Rudy Chang, Jiahong Sun, David H. Cribbs, Todd C. Holmes, Mark J. Fisher and Xiangmin Xu, 15 November 2023, Journal of Neuroinflammation.
DOI: 10.1186/s12974-023-02932-5

Leveraging the broad, collaborative infrastructure and robust resources of the Center for Neural Circuit Mapping, other team members were Rachita Sumbria, co-first author/co-corresponding author and associate professor in the Chapman University School of Pharmacy; Hai Zhang, co-first author and postdoctoral researcher in UCI’s Department of Anatomy & Neurobiology; Rudy Chang, co-first author and Chapman University School of Pharmacy graduate student; Jiahong Sun, postdoctoral researcher at Chapman University; David Cribbs, professor-in-residence at UCI’s Institute for Memory Impairments and Neurological Disorders; and Todd Holmes, UCI professor of physiology & biophysics.

This work was supported by the National Institute on Aging and by the National Institute of Neurological Disorders and Stroke.

Click here to read full SciTech Daily article.

Study identifies new cause of brain bleeds, new treatment target

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What we think we know about brain hemorrhages is only part of the story

Photo: This photo from University of California, Irvine shows red blood cells clogging a capillary in the brain of a mouse. The researchers say the blocking and then clearing of the capillary can lead to microbleeds and brain hemorrhage | University of California, Irvine

By Lois M. Collins, Deseret News, Lcollins@deseretnews.com

New research from the University of California, Irvine, could change the thinking on what causes brain bleeds — and offer the potential to develop new therapies.

Experts have long believed that injury to blood vessels causes brain hemorrhage. But the Irvine team has found that “interactions between aged red blood cells and brain capillaries” can spark microbleeds in brain tissue, too.

The findings were just published in the Journal of Neuroinflammation.

Tiny brain bleeds are associated with stroke, cognitive decline and normal aging, the study says. The authors noted that their own previous work has found that interaction between oxidatively stressed red blood cells and brain capillaries can underlie the development of cerebral microhemorrhages. Such microbleeds are associated with high blood pressure, Alzheimer’s disease and ischemic strokes.

The researchers watched the process in which red blood cells stall in brain capillaries and saw hemorrhage unfold. A news release from UC Irvine said they exposed red blood cells to a chemical that caused oxidative stress, then marked the cells with a fluorescent label and injected them into mice. They then used two methods to watch the fluorescent cells get stuck in the brain capillaries, and how the capillaries were cleared. As the red blood cells moved out of the capillaries, inflammatory cells “engulfed the red blood cells,” leading to a brain hemorrhage.

Capillaries are the body’s tiniest blood vessels. As New Atlas reported, they “employ a clever membranous mechanism to push out any blockages, (but) it’s a system that begins to falter with age.”

Per New Atlas, “The 2010 study that identified this mechanism also found that it becomes 30% to 50% slower in an aging brain and also results in the death of more capillaries.”

“It has always been assumed that in order for cerebral hemorrhage to occur, blood vessels need to be injured or disrupted. We found that increased red blood cell interactions with the brain capillaries represent an alternative source of development,” said co-corresponding author Xiangmin Xu, professor of anatomy and neurobiology and director of Irvine’s Center for Neural Circuit Mapping.

He said detailed examination of how the brain capillaries are cleared and a possible relationship between that process and insufficient blood supply and ischemic stroke is needed to help develop targeted treatments.

Said co-corresponding author Dr. Mark Fisher, professor of neurology in UCI’s School of Medicine, “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.”

Click here to read full Deseret News article.

UC Irvine-led study discovers novel cause of brain hemorrhage

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In vivo microhemorrhages linked to erythrocyte-brain endothelial interactions

By Dr. Prajakta Banik, Tech Explorist

A groundbreaking study led by the University of California, Irvine, has uncovered a surprising cause of brain hemorrhages that doesn’t involve damage to blood vessels, challenging previous beliefs. The research found that interactions between aged red blood cells and brain capillaries can lead to cerebral microbleeds, shedding light on their formation and suggesting new avenues for treatment and prevention.

Published in the Journal of Neuroinflammation, the study observed red blood cells stalling in brain capillaries and the subsequent occurrence of hemorrhages. These microbleeds are linked to conditions more common in older adults, such as hypertension, Alzheimer’s disease, and ischemic stroke.

Co-corresponding author Dr. Mark Fisher, professor of neurology at UCI’s School of Medicine, said, “We have previously explored this issue in cell culture systems, but our current study is significant in expanding our understanding of the mechanism by which cerebral microbleeds develop. Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages at the capillary level.”

The research team treated red blood cells with a chemical, tert-butyl hydroperoxide, inducing oxidative stress. After marking the cells with fluorescence, they injected them into mice. The researchers witnessed the red blood cells getting stuck in brain capillaries through two observation methods. Subsequently, a process called endothelial erythrophagocytosis cleared the cells out. As the cells moved out, microglia inflammatory cells engulfed them, triggering the formation of a brain hemorrhage.

Co-corresponding author Xiangmin Xu, UCI professor of anatomy & and neurobiology and director of the campus’s Center for Neural Circuit Mapping, said, “It has always been assumed that for cerebral hemorrhage to occur, blood vessels need to be injured or disrupted. We found that increased red blood cell interactions with the brain capillaries represent an alternative source of development. We need to examine in detail the regulation of brain capillary clearance and also analyze how that process may be related to insufficient blood supply and ischemic stroke, which is the most common form of stroke, to help advance the development of targeted treatments.”

The UC Irvine-led study is pioneering in revealing a non-vascular cause for brain hemorrhages, significantly advancing our understanding of this complex medical phenomenon. This newfound knowledge holds promise for developing innovative therapeutic interventions and preventive measures, marking a crucial step forward in neurology.

Journal reference:

Zhang, H., Sumbria, R.K., Chang, R. et al. Erythrocyte–brain endothelial interactions induce microglial responses and cerebral microhemorrhages in vivo. Journal of Neuroinflammation. DOI: 10.1186/s12974-023-02932-5

Click here to read full Tech Explorist article.

UC Irvine-led study is first to find brain hemorrhage cause other than injured blood vessels

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Discovery deepens understanding of cerebral microbleeds, may offer new therapeutic targets

Irvine, Calif., Nov. 20, 2023 — A first-of-its-kind study led by the University of California, Irvine has revealed a new culprit in the formation of brain hemorrhages that does not involve injury to the blood vessels, as previously believed. Researchers discovered that interactions between aged red blood cells and brain capillaries can lead to cerebral microbleeds, offering deeper insights into how they occur and identifying potential new therapeutic targets for treatment and prevention.

The findings, published online recently in the Journal of Neuroinflammation, describe how the team was able to watch the process by which red blood cells stall in the brain capillaries and then observe how the hemorrhage happens. Cerebral microbleeds are associated with a variety of conditions that occur at higher rates in older adults, including hypertension, Alzheimer’s disease and ischemic stroke.

“We have previously explored this issue in cell culture systems, but our current study is significant in expanding our understanding of the mechanism by which cerebral microbleeds develop,” said co-corresponding author Dr. Mark Fisher, professor of neurology in UCI’s School of Medicine. “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.”

The team exposed red blood cells to a chemical called tert-butyl hydroperoxide that caused oxidative stress; the cells were then marked with a fluorescent label and injected into mice. Using two different methods, the researchers observed the red blood cells getting stuck in the brain capillaries and then being cleared out in a process called endothelial erythrophagocytosis. As they moved out of the capillaries, microglia inflammatory cells engulfed the red blood cells, which led to the formation of a brain hemorrhage.

“It has always been assumed that in order for cerebral hemorrhage to occur, blood vessels need to be injured or disrupted. We found that increased red blood cell interactions with the brain capillaries represent an alternative source of development,” said co-corresponding author Xiangmin Xu, UCI professor of anatomy & neurobiology and director of the campus’s Center for Neural Circuit Mapping. “We need to examine in detail the regulation of brain capillary clearance and also analyze how that process may be related to insufficient blood supply and ischemic stroke, which is the most common form of stroke, to help advance the development of targeted treatments.”

Leveraging the broad, collaborative infrastructure and robust resources of the Center for Neural Circuit Mapping, other team members were Rachita Sumbria, co-first author/co-corresponding author and associate professor in the Chapman University School of Pharmacy; Hai Zhang, co-first author and postdoctoral researcher in UCI’s Department of Anatomy & Neurobiology; Rudy Chang, co-first author and Chapman University School of Pharmacy graduate student; Jiahong Sun, postdoctoral researcher at Chapman University; David Cribbs, professor-in-residence at UCI’s Institute for Memory Impairments and Neurological Disorders; and Todd Holmes, UCI professor of physiology & biophysics.

This work was supported by the National Institute on Aging under award numbers R01AG062840, R01AG072896, R35127102, RF1 AG065675 and R01NS121246 and by National Institute of Neurological Disorders and Stroke grant R01NS20989.

Click here to read full UCI News press release.

A New Understanding of Brain Hemorrhages: Exploring the Role of Red Blood Cell Interactions

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By , Express Healthcare Management

A groundbreaking study conducted by the University of California, Irvine has unveiled a previously unknown contributor to the formation of brain hemorrhages that does not involve blood vessel injury. The research team discovered that interactions between aged red blood cells (RBCs) and brain capillaries can lead to cerebral microbleeds, shedding light on the underlying mechanisms and potential therapeutic targets for treatment and prevention.

Published in the Journal of Neuroinflammation, the study utilized advanced imaging techniques to observe the process by which RBCs become stalled in brain capillaries and subsequently trigger hemorrhages. Cerebral microbleeds are often associated with conditions that occur more frequently in older adults, such as hypertension, Alzheimer’s disease, and ischemic stroke.

Co-corresponding author Dr. Mark Fisher, a professor of neurology at UCI’s School of Medicine, emphasized the significance of this study in expanding our understanding of how cerebral microbleeds develop. He stated, “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.”

To investigate this link, the research team exposed RBCs to tert-butyl hydroperoxide, a chemical that induces oxidative stress. The treated RBCs, labeled with a fluorescent marker, were then injected into mice. Through two different imaging methods, the researchers observed the RBCs becoming lodged in brain capillaries and subsequently cleared out via endothelial erythrophagocytosis. As the RBCs were cleared, microglia inflammatory cells engulfed them, leading to the formation of brain hemorrhages.

Co-corresponding author Xiangmin Xu, a UCI professor of anatomy and neurobiology, highlighted the implications of their discoveries, stating, “We need to examine in detail the regulation of brain capillary clearance and analyze how this process relates to insufficient blood supply and ischemic stroke to advance the development of targeted treatments.”

This study marks a significant step forward in uncovering the contributors to brain hemorrhages and offers potential avenues for the development of new therapies. By focusing on the interactions between RBCs and brain capillaries, researchers can further explore the regulation of capillary clearance and its connections to other conditions such as ischemic stroke.

FAQ

What are cerebral microbleeds?
Cerebral microbleeds refer to small bleeding spots in the brain, often associated with conditions like hypertension, Alzheimer’s disease, and ischemic stroke. These microbleeds occur at a capillary level and were previously believed to be caused solely by blood vessel injury.

What did the study uncover?
The study discovered that interactions between aged red blood cells and brain capillaries can lead to cerebral microbleeds. By exposing red blood cells to oxidative stress and observing their behavior in mouse models, the researchers observed how the red blood cells become stuck in the capillaries and trigger the formation of brain hemorrhages.

What are the implications of these findings?
The findings of this study have significant clinical implications as they provide a new understanding of the development of cerebral microbleeds. Identifying the link between red blood cell damage and brain hemorrhages at the capillary level opens up potential avenues for targeted treatments and prevention strategies.

What further research is needed in this area?
Further research is needed to delve into the regulation of brain capillary clearance and to analyze its connection to insufficient blood supply and ischemic stroke. Understanding these processes can contribute to the development of more effective treatments for conditions associated with cerebral microbleeds.

Click here to read full Express Healthcare Management article.

A new cause of brain hemorrhage has been identified

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Photo: Depositphotos

By Bronwyn Thompson, New Atlas

In a significant development for brain health, scientists have demonstrated for the first time how hemorrhages can occur due to a faulty interaction between aged red blood cells and narrow capillaries. Until now, the cause of this serious condition has been brain bleeding that results from injured or damaged blood vessels.

“It has always been assumed that in order for cerebral hemorrhage to occur, blood vessels need to be injured or disrupted,” said co-corresponding author Xiangmin Xu, professor at University of California Irvine (UCI). “We found that increased red blood cell interactions with the brain capillaries represent an alternative source of development.”

The team identified how aged red blood cells ‘stall’ in the brain’s narrow network of capillaries, which result in microbleeds at the site. Cerebral microbleeds in older adults have been linked to a higher risk of developing Alzheimer’s disease, hypertension and ischemic stroke.

While capillaries – the smallest blood vessels in the body – employ a clever membranous mechanism to push out any blockages, it’s a system that begins to falter with age.

The 2010 study that identified this mechanism also found that it becomes 30 to 50% slower in an aging brain, and also results in the death of more capillaries.

The team used tert-butyl hydroperoxide to cause oxidative stress to red blood cells, then marked the cells with a fluorescent tag and injected them into the brains of mice. Through two different methods, they saw the red blood cells becoming stuck in the capillaries, before being cleared through the process known as endothelial erythrophagocytosis. But as the cells moved out, microglia inflammatory cells engulfed them, forming a brain hemorrhage.

“We have previously explored this issue in cell culture systems, but our current study is significant in expanding our understanding of the mechanism by which cerebral microbleeds develop,” said co-corresponding author Mark Fisher, professor at UCI’s School of Medicine. “Our findings may have profound clinical implications, as we identified a link between red blood cell damage and cerebral hemorrhages that occurs at the capillary level.”

The team says this finding presents new avenues of research and potential treatment to help an aging brain maintain capillary function and to prevent those aged cells from stalling along this essential transport route.

“We need to examine in detail the regulation of brain capillary clearance and also analyze how that process may be related to insufficient blood supply and ischemic stroke, which is the most common form of stroke, to help advance the development of targeted treatments,” Fisher added.

The study was published in the Journal of Neuroinflammation.

Source: University of California Irvine

Click here to read full New Atlas article.

UCI Samueli School of Engineering 2022-23 Dean’s Report

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The e+ Equation

Inside
In this issue of the UCI Samueli School of Engineering 2022-23 Dean’s Report, you will learn how collaboration inspires the school’s EngineeringPlus approach to its mission of education, research and partnerships. The inclusive concept involves looking beyond one’s own expertise to engineer innovative solutions for the grand challenges facing society. Please enjoy reading about UCI engineering researchers, students and alumni who use their expertise, imagination and creativity to enhance the human experience.

Faculty Accolades
Early Career – MAXIM SHCHERBAKOV, DARPA Young Faculty

MOMS
Biomedical engineers MICHELLE KHINE and BERNARD CHOI have combined their technologies to create the Maternal Obstetrics Monitoring Sock, a low-cost, point-of-care system to monitor pregnant women for preeclampsia, anemia and hemorrhage. According to the NIH, pregnancy and childbirth complications are a major global health problem and result in the deaths of more than 800 women and 7,000 newborns each day. The smart sock works by integrating the soft beat-to-beat blood pressure sensor that Khine has been developing in her lab with the photonic anemia and hemorrhage sensor from Choi’s lab. The health data is wirelessly transmitted to a smartphone and can alert patients if necessary. The technology is not significantly affected by skin pigmentation or motion artifacts and can be manufactured for under $100.

About the Dean’s Report
The UCI Samueli School of Engineering Dean’s Report is an annual magazine that highlights exciting research, news and faculty accomplishments from the prior year. Issued in the fall, it also conveys a new theme each year to coincide with the school’s progress and the Dean’s priorities.

Click here to read the full UCI Samueli School of Engineering 2022-23 Dean’s Report.