Endoglin: Its Role in Health, Disease, and Medicine

Endoglin is a protein found on the surface of cells throughout the body, particularly on endothelial cells, which form the lining of blood vessels. It is also referred to as CD105. This protein is involved in various cellular processes.

Endoglin’s Biological Role

Endoglin acts as a co-receptor for the transforming growth factor-beta (TGF-beta) superfamily, proteins that regulate cell growth, differentiation, and tissue repair. It interacts with TGF-beta type I receptors, such as ALK1 and ALK5, and a TGF-beta type II receptor, modulating the signals these growth factors send into cells. This modulation is important for functions including angiogenesis, the formation of new blood vessels.

Endoglin is highly expressed on activated endothelial cells, playing a role in both developmental and adult angiogenesis. It influences endothelial cell proliferation and migration, which are important for blood vessel development and repair. Studies in mice indicate that a complete absence of endoglin leads to embryonic death due to impaired development of the vascular network and issues with cardiac development. Endoglin also contributes to maintaining the structural integrity of existing blood vessels.

Endoglin and Hereditary Hemorrhagic Telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is a genetic disorder linked to mutations in the ENG gene, which codes for endoglin. These mutations lead to HHT type 1, affecting an estimated 1 in 5,000 to 10,000 people worldwide, though it is often underdiagnosed. The ENG gene is located on chromosome 9.

Mutations in the ENG gene can lead to a shortage of functional endoglin. This deficiency interferes with the proper development of boundaries between arteries and veins, leading to abnormal blood vessel formations. These malformations include telangiectasias, which are small, dilated blood vessels appearing as red or purple spots on the skin or mucous membranes, often on the lips, nose, fingers, or inside the mouth.

Larger abnormal blood vessels, called arteriovenous malformations (AVMs), can also form in organs like the lungs, brain, liver, and gastrointestinal tract. The most common symptom of HHT is frequent nosebleeds, affecting approximately 90% of individuals, often starting in childhood. Bleeding from gastrointestinal telangiectasias can lead to dark stools or blood in the stool and severe iron deficiency anemia, causing fatigue and shortness of breath. Lung AVMs can cause low blood oxygen levels, headaches, fatigue, and exercise intolerance, and in rare cases, can rupture, leading to coughing up blood. Brain AVMs can cause headaches or seizures, and in rare instances, a life-threatening brain hemorrhage.

Endoglin’s Broader Disease Connections

Beyond HHT, endoglin is involved in other diseases, notably cancer and pre-eclampsia. In cancer, endoglin expression is often elevated in the blood vessels within and around tumors, indicating its role in tumor angiogenesis, the formation of new blood vessels that supply tumors with nutrients and oxygen. This makes it a marker for tumor-related angiogenesis.

The overexpression of endoglin can contribute to tumor growth and the spread of cancer cells to other parts of the body, a process known as metastasis. Elevated levels of soluble endoglin in the bloodstream have been observed in various solid tumors, including prostate, breast, and colorectal cancers, and are associated with advanced metastatic disease. In pre-eclampsia, a serious pregnancy complication characterized by high blood pressure and protein in the urine, altered endoglin levels contribute to vascular dysfunction.

In pre-eclampsia, the placenta releases increased amounts of soluble endoglin into the mother’s circulation. This soluble form of endoglin can inhibit TGF-beta1 binding to its receptors, leading to dysregulated TGF-beta signaling. This disruption impairs endothelial cell function, contributing to vascular issues observed in pre-eclampsia, including increased vascular resistance and hypertension.

Targeting Endoglin in Medicine

Endoglin’s distinct expression patterns in various diseases make it a target for medical interventions. Its elevated presence on actively proliferating endothelial cells, particularly in tumor angiogenesis, supports its role as a biomarker for certain conditions, including cancer. For instance, increased plasma endoglin levels in lung cancer patients have been linked to a better prognosis and enhanced sensitivity to certain chemotherapies.

Therapeutic strategies are being developed to target endoglin, especially in cancer therapy, with the goal of inhibiting tumor growth and metastasis. Anti-endoglin antibodies, such as TRC105, are being explored in clinical trials as anti-angiogenic therapies. These antibodies can suppress tumor metastasis and the growth of primary tumors by targeting the blood vessels that supply them. Research also investigates combining anti-endoglin therapies with other treatments, like MEK inhibitors, to further reduce tumor cell growth and angiogenesis.

While the primary focus of endoglin-targeting therapies has been cancer, research also explores its potential in HHT and pre-eclampsia. For HHT, approaches aim to enhance the expression or function of endoglin and related proteins to counteract the effects of genetic mutations. In pre-eclampsia, targeting the activated endothelin system, which is influenced by endoglin, is being considered as a treatment option to mitigate hypertension and proteinuria.

Does Diabetes Cause Cirrhosis? The Connection Explained

What Do Pap Smear Images Reveal About Your Cells?

How to Use a CGM for Insulin Resistance