CDH5 - cadherin 5 | Elisa - Clia - Antibody - Protein

Background

Cadherin-5 (CDH5), also known as VE-cadherin (vascular endothelial cadherin), is a calcium-dependent adhesion protein primarily found in endothelial cells, which line blood and lymphatic vessels. It plays a critical role in maintaining the integrity and permeability of blood vessels by facilitating cell-cell adhesion between endothelial cells. CDH5 is essential for normal vascular development, and disruptions in its expression or function have been linked to various diseases, including cancer, cardiovascular diseases, and inflammatory conditions. As a classical cadherin, CDH5 belongs to a larger family of transmembrane proteins characterized by their cadherin repeats, which enable homophilic (same-type cell) binding and the formation of stable adherens junctions.

Protein Structure

CDH5 is a transmembrane glycoprotein composed of approximately 784 amino acids and has a molecular weight of about 88 kDa. The protein is divided into several structural domains that contribute to its adhesive functions and signaling roles:

Extracellular Domain (ECD):

• The extracellular domain of CDH5 consists of five cadherin repeats (EC1 to EC5). These repeats, also known as cadherin domains, are responsible for calcium-dependent homophilic binding to cadherins on adjacent endothelial cells.
• Calcium ions stabilize the cadherin repeats, which prevents the domain from unfolding, maintaining a rigid structure necessary for adhesion. Each cadherin repeat has a β-barrel structure, contributing to the strong, cohesive binding between endothelial cells.
• The first cadherin repeat (EC1) contains residues critical for homophilic binding, facilitating CDH5’s attachment to neighboring VE-cadherin molecules on adjacent cells, forming the adherens junctions essential for vascular stability.

Transmembrane Domain (TMD):

• The transmembrane domain of CDH5 is a single-pass α-helix that anchors the protein into the plasma membrane. This hydrophobic region allows for the integration of CDH5 into the lipid bilayer, positioning the extracellular domain outside the cell and the intracellular domain within the cell.
• The TMD also enables the lateral clustering of CDH5 molecules within the cell membrane, which is essential for strengthening cell-cell junctions in endothelial cells.

Cytoplasmic Domain:

• The cytoplasmic tail of CDH5 interacts with intracellular proteins, including β-catenin, p120-catenin, and α-catenin. These interactions link CDH5 to the actin cytoskeleton, which is critical for maintaining cell shape, signaling, and cell stability.
• The cytoplasmic domain also serves as a signaling hub, transmitting signals from the extracellular matrix to the cell’s interior and coordinating cellular responses to mechanical and chemical changes in the environment.

Classification and Subtypes

CDH5 is part of the cadherin superfamily, specifically the classical cadherins, known for their role in calcium-dependent cell-cell adhesion. It belongs to type II cadherins, which are differentiated by their specific structure and lack of the HAV (histidine-alanine-valine) motif found in type I cadherins. CDH5 does not have recognized subtypes but is highly conserved and specifically expressed in endothelial cells across species. Due to its selective expression in endothelial cells, CDH5 is also referred to as endothelial-specific cadherin.

Function and Biological Significance

Cell-Cell Adhesion in Endothelial Cells:

• CDH5 is a central component of adherens junctions in endothelial cells, facilitating homophilic binding that forms tight connections between cells. These junctions maintain vascular barrier integrity, control vascular permeability, and protect against uncontrolled leakage of blood components.
• Through adherens junctions, CDH5 helps to maintain endothelial cell morphology, enabling endothelial cells to form a continuous monolayer that is essential for blood vessel integrity. Loss of CDH5 function or decreased expression weakens these junctions, leading to increased vascular permeability and tissue edema.

Signaling in Angiogenesis and Vascular Development:

• CDH5 is involved in angiogenesis, the process by which new blood vessels form from existing ones. It regulates endothelial cell proliferation and migration, which are essential for forming and remodeling the vascular network.
• Beyond its adhesive properties, CDH5 acts as a signaling receptor. Through interactions with β-catenin and other signaling molecules, CDH5 influences pathways like VEGF (vascular endothelial growth factor) signaling, which promotes endothelial cell survival and angiogenesis.
• CDH5 also regulates signaling pathways involving Rho GTPases, such as RhoA and Rac1, which are critical for cytoskeletal organization, cell polarity, and cell motility. These functions are essential for the coordinated migration and alignment of endothelial cells during vascular growth and repair.

Role in Vascular Permeability:

• By forming adherens junctions, CDH5 controls the selective permeability of blood vessels, regulating the passage of solutes, proteins, and immune cells between the bloodstream and tissues. This selective permeability is vital for maintaining tissue homeostasis and protecting tissues from pathogens and other harmful agents.
• During inflammation, CDH5 expression is downregulated, or the protein is phosphorylated, weakening adherens junctions and increasing vascular permeability. This allows immune cells to migrate to sites of infection or injury, although excessive permeability can lead to edema and tissue damage.

Endothelial Cell Survival and Apoptosis:

• CDH5 contributes to endothelial cell survival by mediating survival signals and stabilizing cell-cell contacts. Disruption of CDH5-mediated junctions can lead to endothelial cell apoptosis, impairing vascular function.
• Through interactions with survival pathways, CDH5 also aids in maintaining endothelial cell viability in response to stress and injury, highlighting its protective role in vascular homeostasis.

Clinical Issues

Cancer and Tumor Metastasis:

• CDH5 dysregulation is implicated in cancer progression and metastasis. Tumor-associated endothelial cells often exhibit altered CDH5 expression, which facilitates the passage of tumor cells through the vascular endothelium (a process known as transendothelial migration). This leads to cancer cells disseminating from primary tumors to distant sites, promoting metastasis.
• Targeting CDH5 in tumor vasculature is being explored as a therapeutic strategy to prevent tumor cell invasion and metastasis. Anti-CDH5 therapies may help reduce tumor vascularization and restrict cancer cell access to the circulatory system.

Cardiovascular Diseases:

• In cardiovascular diseases such as atherosclerosis and hypertension, endothelial dysfunction, including impaired CDH5 function, contributes to increased vascular permeability and inflammation. Elevated levels of inflammatory cytokines can disrupt CDH5-mediated junctions, leading to increased vascular leakage and inflammation within blood vessel walls.
• Restoring CDH5 function or expression in damaged vasculature is being investigated as a potential therapy for improving endothelial integrity and reducing inflammatory damage in cardiovascular diseases.

Inflammation and Sepsis:

• During systemic inflammation and sepsis, cytokines and other inflammatory mediators downregulate CDH5 or disrupt its interactions with the cytoskeleton, causing endothelial barrier dysfunction. This vascular permeability results in widespread tissue edema and contributes to organ failure in severe sepsis.
• Strategies to stabilize CDH5 interactions during inflammation are being researched to protect vascular integrity and prevent the severe consequences of barrier breakdown in inflammatory and infectious diseases.

Angiogenesis-Related Disorders:

• CDH5’s role in angiogenesis makes it relevant in disorders involving abnormal blood vessel formation, such as retinopathy and rheumatoid arthritis. Aberrant regulation of CDH5-mediated signaling can lead to excessive or insufficient blood vessel formation, contributing to disease progression in these conditions.

Summary

Cadherin-5 (CDH5), or VE-cadherin, is a crucial transmembrane glycoprotein primarily expressed in endothelial cells. It mediates calcium-dependent cell-cell adhesion, forming adherens junctions that maintain vascular integrity and control vascular permeability. Structurally, CDH5 consists of an extracellular domain with five cadherin repeats, a transmembrane domain, and a cytoplasmic domain that interacts with proteins like β-catenin, linking CDH5 to the actin cytoskeleton and signaling pathways. Functionally, CDH5 is essential for maintaining endothelial barrier integrity, regulating angiogenesis, controlling vascular permeability, and supporting endothelial cell survival. Clinically, dysregulated CDH5 expression or function contributes to diseases such as cancer, cardiovascular disorders, and inflammatory conditions. Due to its central role in vascular biology, CDH5 remains a critical focus in developing therapies for vascular-related diseases, cancer metastasis, and inflammatory disorders.