Endoglin (CD105) is a large transmembrane glycoprotein found primarily on the surface of endothelial cells lining blood vessels. It is fundamental to the body’s vascular system, acting as a gatekeeper that controls cellular responses to growth signals. Proper function is necessary for the formation and maintenance of stable blood vessels. Disruptions to Endoglin’s activity, whether genetic or physiological, are linked to severe diseases, positioning it as a promising target for diagnostic tools and therapeutic interventions.
Endoglin Structure and Core Cellular Function
Endoglin is a type I membrane glycoprotein that exists on the cell surface as a homodimer. Encoded by the ENG gene, it is highly expressed on endothelial cells, particularly when they are actively growing. Its structure includes a large extracellular domain, a transmembrane region anchoring it to the cell membrane, and a short intracellular tail.
The primary function of Endoglin is to act as an accessory receptor, or co-receptor, for the Transforming Growth Factor Beta (TGF-\(\beta\)) superfamily of signaling molecules. This superfamily includes TGF-\(\beta\) 1 and 3, and Bone Morphogenetic Proteins (BMPs), such as BMP-9 and BMP-10. Endoglin binds to these growth factors and modulates how the main signaling receptors respond, rather than initiating signaling itself.
By associating with primary TGF-\(\beta\) receptors, Endoglin acts like a molecular switch, dictating which specific signaling pathway is activated inside the cell. This modulation of the TGF-\(\beta\) pathway controls cell behaviors such as proliferation, migration, and differentiation. Endoglin specifically interacts with the type I receptor Activin Receptor-Like Kinase 1 (ALK1), which is a major determinant of endothelial cell growth and vascular network integrity.
Endoglin and Vascular Health Regulation
The regulation of blood vessel growth and stability is one of Endoglin’s most significant physiological roles. In healthy adults, Endoglin expression is low on resting endothelial cells, but levels rise sharply in activated cells, such as during the formation of new blood vessels. This process, known as angiogenesis, is necessary for wound healing and tissue repair.
Endoglin helps fine-tune the signaling pathways that govern endothelial cell behavior during capillary formation. It promotes a balance between the growth of new vessels and the maturation and stabilization of existing ones. This balance ensures that new vessels are structurally sound parts of the circulatory system, not just leaky tubes.
When Endoglin activity is properly balanced, it supports the integrity and stability of the vascular wall. Conversely, disruption to this balance, whether over- or under-functioning, can lead directly to pathological conditions. This is because Endoglin’s presence is required for the proper recruitment of supporting cells, such as pericytes and vascular smooth muscle cells, which stabilize the new vessel walls.
Endoglin in Hereditary and Pregnancy-Related Disorders
Endoglin’s influence is demonstrated in two distinct disease states: one caused by an inherited genetic defect and the other by an acquired imbalance during pregnancy. A defect in the ENG gene causes Hereditary Hemorrhagic Telangiectasia Type 1 (HHT1), an autosomal dominant disorder. Patients with HHT1 have insufficient functional Endoglin protein, resulting in a miscommunication of growth signals within the blood vessel walls.
This vascular miscommunication causes the formation of abnormal blood vessels, specifically telangiectasias and arteriovenous malformations (AVMs). Telangiectasias are small, dilated blood vessels near the skin’s surface. AVMs are larger, direct connections between arteries and veins that bypass the capillary bed, leading to serious consequences like frequent nosebleeds and internal bleeding.
A different mechanism is at play in Preeclampsia, a condition that develops during pregnancy, characterized by high blood pressure and signs of organ damage. In this case, the mother’s circulation accumulates high levels of soluble Endoglin (sEng). sEng is a truncated form of the protein, cleaved from the cell surface by enzymes, that circulates freely in the bloodstream.
The circulating sEng acts as a decoy, binding to growth factors like BMP-9 and preventing them from reaching full-length Endoglin receptors on endothelial cells. This disrupts the signaling required for maintaining a healthy maternal vascular system and placental blood flow. The result is widespread endothelial dysfunction, leading to the high blood pressure and organ damage characteristic of Preeclampsia.
Endoglin’s Influence on Cancer and Metastasis
Endoglin is involved in the biology of many cancers, acting as a promoter of tumor growth and spread. Its expression is significantly increased on the endothelial cells that form the new blood vessels supplying a tumor, a process known as tumor angiogenesis. This high concentration of Endoglin on tumor vasculature makes it an established marker for active blood vessel growth.
The presence of Endoglin helps tumors develop the chaotic, leaky network of blood vessels needed for survival and expansion. These vessels provide tumor cells with oxygen and nutrients, and serve as a route for cancer cells to escape into the wider circulation. This involvement in vessel development makes Endoglin an attractive target for therapies aimed at starving the tumor.
Endoglin also plays a role in metastasis, the process where cancer cells spread to distant organs. It influences the ability of tumor cells to navigate the blood vessel lining when they enter the circulation and when they exit to colonize a new site. In several malignancies, including breast and prostate cancers, the level of Endoglin expression correlates with increased tumor aggressiveness and a poorer prognosis.
Endoglin as a Diagnostic Marker and Therapeutic Target
The distinct roles of Endoglin in disease have been translated into practical medical applications for both diagnosis and therapy. Measuring the levels of soluble Endoglin (sEng) in the bloodstream is useful as a diagnostic and prognostic marker. Elevated sEng levels are associated with the development of Preeclampsia and can serve as an early indicator of the condition’s severity in pregnant women.
In oncology, Endoglin expression on tumor-associated blood vessels acts as a marker that can predict the rate of tumor growth and the likelihood of metastasis. High Endoglin levels are often a sign of aggressive disease and help clinicians determine the most appropriate treatment strategy. This diagnostic utility is based on the protein’s unique expression pattern in pathology.
As a therapeutic target, Endoglin’s location primarily on the surface of diseased cells, such as those in tumor vessels, makes it highly accessible to drug intervention. One strategy involves the use of monoclonal antibodies, such as TRC105, designed to specifically bind to and neutralize the Endoglin protein. By blocking Endoglin, these antibodies aim to normalize the chaotic tumor blood vessels, making them less supportive of tumor growth and more susceptible to chemotherapy. This approach selectively disrupts the tumor’s blood supply, cutting off the resources needed for survival.