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Study Identifies A New Potential Target For Treating Vascular Disease

Vascular diseases, including myocardial infarction, stroke, renal failure, and peripheral vascular disease, continue to account for one third of all mortality in the United States, Europe, and the developing world (World Health Organization, 2021). Vascular smooth muscle cell (VSMC) activation plays a crucial role in the development of multiple vascular diseases.

In a novel study in The American Journal of Pathology, researchers found that when fragile-X related protein-1 (FXR1) is absent, VSMC proliferate more slowly, become senescent, and scar tissue (neointima) development is reduced. Therefore, drugs targeting FXR1 may treat vascular proliferative diseases.

"Our lab previously reported that expression of FXR1, a muscle-enhanced RNA binding protein that appears to decrease inflammatory transcripts, is increased in injured arteries and in plaque VSMC in human aortas," explained lead investigator Michael V. Autieri, Ph.D., Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, U.S..

"However, the role of FXR1 expression in the vascular response to injury had not yet been studied in a relevant animal model of vascular disease, and so we designed our study to explore this further."

To extend their understanding of the impact of the absence of FXR1, investigators performed RNA-sequencing on FXR1-depleted human VSMCs. Their results suggest that FXR1 appears to stabilize a group of transcripts involved in control of the cell cycle, most of which are associated with proliferation and cell division. In addition, they noted an increase in beta galactosidase and gamma H2AX, molecules indicative of cell senescence.

Next, to understand how the absence of FXR1 would affect vascular occlusive disease, they developed a mouse model to specifically deplete FXR1 in the smooth muscles upon drug induction. The mice were subjected to carotid ligation, which is a model of vascular stenosis. Drug-induced depletion of FXR1 in smooth muscle cells protected the mice against neointima formation following injury. Injured arteries had a gene expression profile similar to human VSMC following FXR1 knockdown.

"These results are the first to suggest that in addition to destabilization of inflammatory transcripts, FXR1 may stabilize cell cycle related genes in VSMC, and absence of FXR1 leads to induction of a senescent phenotype. This supports the hypothesis that FXR1 may mediate vascular disease by regulating stability of proliferative mRNA in VSMC," commented Dr. Autieri.

The fact that FXR1 stabilized this group of transcripts, while it normally is regarded as an RNA-binding protein that destabilizes transcripts, was surprising to investigators. Additionally, while they expected to see a difference in the knockout mouse phenotype compared to controls, they did not expect such a dramatic result.

"Because we have seen that in the absence of FXR1, VSMC have significantly reduced proliferation and become senescent, drugs that target FXR1 may have implications for modalities to combat vascular proliferative diseases such as atherosclerosis, restenosis, hypertension, and abdominal aortic aneurysm. Given the global increase in cardiovascular diseases in an aging and increasingly sedentary population, it is critical to do everything we can to investigate potential genes and targets that may be exploited to influence disease pathology," Dr. Autieri concluded.

More information: Cali B. Corbett et al, Genetic Deletion of FXR1 Reduces Intimal Hyperplasia and Induces Senescence in Vascular Smooth Muscle Cells, The American Journal of Pathology (2023). DOI: 10.1016/j.Ajpath.2023.01.006

Citation: Study identifies a new potential target for treating vascular disease (2023, May 2) retrieved 30 May 2023 from https://medicalxpress.Com/news/2023-05-potential-vascular-disease.Html

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What To Know About End Stage Peripheral Vascular Disease

End stage peripheral vascular disease can put people at risk of limb amputation or life threatening complications. Treatment typically involves surgery.

Peripheral vascular disease (PVD), also known as peripheral artery disease, is a condition that restricts blood flow to a person's limbs and other body parts. It can affect any blood vessel outside the heart. However, it most commonly affects the legs. Some organs, such as the brain, may not get enough blood flow to work properly.

The most severe forms, or end stages, of PVD, can lead to critical limb ischemia (CLI) and acute limb ischemia (ALI). People with CLI or ALI are at risk of limb loss or gangrene.

This article discusses PVD and how the condition progresses to its end stage. It also discusses the causes, symptoms, treatments, and complications of end stage PVD.

People in the early stages of PVD may experience no symptoms. As PVD progresses, symptoms typically worsen.

There are two main classification systems for describing the stages and symptoms of PVD — the Rutherford and Fontaine systems:

  • Rutherford Category 0 or Fontaine Stage 1: At this stage, a person with PVD has no symptoms.
  • Rutherford Categories 1–3 or Fontaine Stages 2a and 2b: PVD symptoms include mild to severe claudication. "Claudication" is the medical term for pain, cramping, or fatigue in a person's legs after sustained exercise or walking. The pain stops after a person stands still for a few minutes.
  • Rutherford Category 4 or Fontaine Stage 3: People have ischemic resting pain — severe pain in their legs and feet when they are resting. They may also have sores on their legs and feet that do not heal. Ischemic resting pain is an indicator of CLI.
  • Rutherford Categories 5 and 6 or Fontaine Stage 4: In these end stages of PVD, people may have some minor tissue loss and ulcers forming on the skin of their legs. They may also have gangrene, a serious condition in which the body tissues start to die as a result of a lack of blood supply.
  • Other symptoms in one or both legs, such as the following, may indicate earlier stages of PVD:

  • muscle atrophy, or leg weakness
  • leg numbness, pain, or heaviness when walking or climbing stairs
  • leg hair loss
  • smooth, shiny, leg skin
  • a lack of toenail growth
  • leg skin that feels cool to the touch
  • weak pulse or no pulse in the feet
  • cold or numbness in the toes
  • erectile dysfunction, especially among those who have diabetes
  • The most common cause of end stage PVD is worsening atherosclerosis. This is when plaque buildup blocks or narrows a person's blood vessels, causing the loss of some or all blood circulation to the limbs.

    If the plaque buildup entirely blocks blood circulation to a person's limbs, it can cause end stage PVD.

    Factors that raise a person's risk of PVD include:

    Symptoms of end stage PVD include the symptoms of CLI, such as:

  • ischemic resting pain
  • tissue loss
  • gangrene
  • End stage PVD symptoms also include symptoms of ALI, such as:

  • leg pain
  • pallor, which means a person's skin looks lighter than their typical complexion
  • lack of a pulse in the legs
  • poikilothermia, or cold legs
  • paresthesias, or a tingling or prickling "pins and needles" sensation in the legs
  • leg paralysis, with a loss of sensation and ability to move the legs, in more severe cases of PVD
  • If a person believes they may be experiencing the symptoms of CLI or ALI, they should immediately seek medical attention. Doctors classify CLI and ALI as medical emergencies. People with CLI or ALI need an emergency consultation with a doctor to avoid limb amputation.

    Doctors typically diagnose CLI if a person has been experiencing symptoms for at least 2 weeks. If symptoms have been present for less time, then doctors will generally consider the condition ALI.

    Doctors consider the following when diagnosing PVD:

  • a person's risk factors
  • the results of physical exams
  • a person's description of their symptoms
  • If PVD is end stage, doctors will typically use surgery to treat CLI or leg pain.

    Doctors can use endovascular surgery to improve the blood flow to a person's leg. During this type of surgery, doctors inject a long, thin, flexible tube called a catheter through a person's skin into their blood vessels, or arteries. They then use the catheter to operate on the blood vessels.

    PVD may have life threatening complications. Blockages in a person's blood vessels or arteries can affect other areas of their body, such as their heart and brain. They may then develop other forms of cardiovascular disease, leading to:

    Other possible complications of PVD include:

    Around 50% of people with end stage PVD have a life expectancy of 5 years from the time of diagnosis.

    A buildup of plaque in a person's blood vessels can lead to end stage PVD. This condition tends to develop over time with worsening symptoms.

    Without treatment, PVD can cause serious or life threatening complications.

    Doctors can treat end stage PVD with surgery. Most risks for PVD involve lifestyle factors. Lifestyle strategies such as quitting smoking, making efforts to reach or maintain a moderate weight, and eating a healthy and balanced diet can help reduce the risk of PVD progressing to end stage.


    What Is An Aortobifemoral Bypass?

    An aortobifemoral bypass is a surgery that's done to redirect your blood flow around a large, blocked artery in your groin or abdomen. It increases the blood flow to your legs. It's a major surgery that is usually only done if you're in danger of losing a leg or if your symptoms are severe.

    Your surgeon will use an artificial blood vessel to bypass the clogged artery. It is shaped like an upside-down Y. The bottom of the Y will be sewn to your aorta above the diseased part of the artery in your abdomen. The two top parts of the Y will be attached to the femoral arteries below the blocked area.  ‌

    The femoral arteries are the large arteries in each of your thighs. After this graft is put in, the blood will be able to flow from your aorta to your femoral arteries by going around the clogged area.

    You may need an aortobifemoral bypass if one of the major arteries in your abdomen, pelvis, or groin is blocked by a buildup of fatty deposits on your artery walls. The aorta is the largest artery in your body. It's in your abdomen. It splits to form the iliac arteries in your pelvis. These arteries are called the femoral arteries when they reach your thighs.‌

    A buildup of fatty deposits in your artery is called atherosclerosis. It's called peripheral artery disease (PAD) when atherosclerosis affects the arteries leading to your arms, legs, stomach, or head. It usually affects the arteries leading to your legs.

    ‌The tissues in your legs can't get enough oxygen if the blood flow is blocked by peripheral artery disease. When this happens, it might cause:

  • Pain that gets worse if you exercise
  • Sores that won't heal on your legs or feet
  • Nerve damage
  • Gangrene, which is when your tissues die because they don't get enough blood
  • Dry, itchy, scaly, or brown skin on your legs or feet
  • The need for amputation of your leg
  • The most serious risk of an aortobifemoral bypass is a heart attack. Other complications that can develop are:

  • Bleeding
  • Infection
  • Hematoma, which is a collection of blood outside of a blood vessel
  • Kidney problems
  • Breathing problems
  • Hernia
  • Blood clot in your leg
  • Swelling in the wall of the artery caused by a small hole
  • Aortoenteric fistula, which is an abnormal connection between the aorta and the gastrointestinal system
  • About 80% of people who have aortobifemoral bypass surgery have relief of symptoms and successful bypass of the blocked artery after surgery. Most people don't have pain when they are resting. Their pain is greatly reduced when they are walking, as well. If you smoke, your outlook will be better if you quit smoking before the surgery and don't start back.

    Before you have an aortobifemoral bypass, you should try other ways to treat your peripheral artery disease, including:

    Anyone who can't have general anesthesia shouldn't have an aortobifemoral bypass. You may also be at an increased risk of complications if you have any of the following issues:

  • Significant heart disease
  • A recent stroke
  • A recent heart attack
  • Multiple previous surgeries in your abdominal area
  • Retroperitoneal fibrosis, which is a rare disease that causes fibroids in your abdominal cavity
  • End-stage kidney disease
  • A horseshoe kidney, which is when you were born with your kidneys fused together
  • You will be sore and tired for several weeks after your surgery. You'll be able to do many of your normal activities after 4 to 6 weeks. It may take you up to 2 to 3 months to fully recover. The following tips will help you take care of yourself at home: 

  • Get plenty of sleep.
  • Rest when you feel tired.
  • Try to walk a little more each day.
  • Avoid strenuous activities until your doctor says it's okay.
  • Avoid straining to lift anything for 6 weeks.
  • Follow your doctor's instructions about breathing exercises, showering, and activity.
  • Call your doctor if you have any of the following symptoms after surgery:  

  • Fever, chills, or other signs of infection
  • Nausea or vomiting
  • Cough, shortness of breath, or chest pain
  • Redness, swelling, pain, bleeding, or discharge from your incision site
  • Pain that can't be controlled with your medicine
  • Pain or swelling in your legs or feet
  • Problems when you urinate, including pain, urgency, frequency, or bleeding
  • Legs that are pale, blue, cold, tingly, or numb





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