The blood vessel-specific proteomeThe blood vessel transcriptomeProtein expression of genes elevated in blood vesselGene expression shared between blood vessel and other tissuesBlood vessel functionBlood vessel histologyBackgroundRelevant links and publications

Tissue methods

The blood vessel-specific proteome

The blood vessel transcriptome

Transcriptome analysis of the blood vessel can be visualized with regard to the specificity and distribution of transcribed mRNA molecules (Figure 1). Specificity illustrates the number of genes with elevated or non-elevated expression in the blood vessel compared to other tissues. Elevated expression includes three subcategory types of elevated expression:

• Tissue enriched: At least four-fold higher mRNA level in blood vessel compared to any other tissues.
• Group enriched: At least four-fold higher average mRNA level in a group of 2-5 tissues compared to any other tissue.
• Tissue enhanced: At least four-fold higher mRNA level in blood vessel compared to the average level in all other tissues.

Distribution, on the other hand, visualizes how many genes have, or do not have, detectable levels (nTPM≥1) of transcribed mRNA molecules in the blood vessel compared to other tissues. As evident in Table 1, all genes elevated in blood vessel are categorized as:

• Detected in single: Detected in a single tissue
• Detected in some: Detected in more than one but less than one-third of tissues
• Detected in many: Detected in at least a third but not all tissues
• Detected in all: Detected in all tissues

Figure 1. (A) The distribution of all genes across the five categories based on transcript specificity in blood vessel as well as in all other tissues. (B) The distribution of all genes across the six categories, based on transcript detection (nTPM≥1) in blood vessel as well as in all other tissues.

As shown in Figure 1, 300 genes show some level of elevated expression in blood vessel compared to other tissues. The three categories of genes with elevated expression in blood vessel compared to other organs are shown in Table 1.

Table 1. The number of genes in the subdivided categories of elevated expression in blood vessel.

Protein expression of genes elevated in blood vessel

In-depth analysis of the elevated genes in blood vessel using antibody-based protein profiling allowed us to visualize the expression patterns of these proteins in different functional compartments, including genes involved in contraction, structural integrity, coagulation, wound healing, and transmembrane transport.

Proteins related to contraction and structural integrity

Smooth muscle, elastic tissue, and collagen are major structural components of blood vessels that are present at varying proportions depending on the type of blood vessel. Smooth muscle facilitates the regulation of blood pressure by contracting or relaxing, while elastic tissue and collagen give structure and flexibility. Calponin 1 (CNN1) is a protein thought to be involved in the regulation of muscle contraction by activating actin binding. Elastin (ELN) is one of two proteins that make up elastic fibers, which are especially important in elastic arteries that receive large blood pressure waves. COL8A1 encodes one of the chains of type VIII collagen, a component of the very thin subendothelial tissue that supports the endothelium.

CNN1
ELN
COL8A1

Proteins related to coagulation and wound healing

One of the many functions of the endothelium, which lines the inside of the blood vessels, is to regulate blood coagulation. Under normal circumstances, it secretes anticoagulant factors, while in case of tissue damage, it secretes factors that promote clotting. PTGIS catalyzes the biosynthesis of eicosanoids such as prostacyclin, an anticoagulation factor that prevents clotting by inhibiting platelet aggregation. Fibronectin (FN1), on the other hand, plays a crucial role in wound healing by forming a blood clot together with fibrin. Endothelial cells also express cell-adhesion molecules to facilitate the migration of circulating lymphocytes across the blood vessel and into the site of tissue damage. An example of such a cell-adhesion molecule is AOC3, which otherwise functions as a catalyst for the oxidative conversion of amines to aldehydes.

PTGIS
FN1
AOC3

Proteins related to transmembrane transport

Endothelial cells also transport molecules from the blood to the surrounding tissues using specialized organelles and transport proteins. An example of a gene elevated in blood vessels is AQP1, which encodes a channel protein that facilitates the transport of water across the cell membrane. Another example is CLIC4, a protein with several putative functions, including formation of chloride channels that are involved in transepithelial transport.

AQP1
CLIC4

Gene expression shared between blood vessel and other tissues

There are 29 group enriched genes expressed in blood vessel. Group enriched genes are defined as genes showing a 4-fold higher average level of mRNA expression in a group of 2-5 tissues, including blood vessel, compared to all other tissues.

To illustrate the relation of blood vessel tissue to other tissue types, a network plot was generated, displaying the number of genes with a shared expression between different tissue types.

Figure 2. An interactive network plot of the blood vessel enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of blood vessel enriched genes and orange nodes represent the number of genes that are group enriched. The sizes of the red and orange nodes are related to the number of genes displayed within the node. Each node is clickable and results in a list of all enriched genes connected to the highlighted edges. The network is limited to group enriched genes in combinations of up to 4 tissues, but the resulting lists show the complete set of group enriched genes in the particular tissue.

As shown in figure 2, blood vessel shares most genes with brain (n=8), heart muscle (n=6), and choroid plexus (n=5). An example of a gene enriched in both brain and blood vessels is HTR1B, a receptor for serotonin, which plays an important role in vasoconstriction of arteries in the brain and other tissues. A gene shared with heart tissue and choroid plexus is KCNA5, a voltage-gated channel that is important for transport of potassium ions across excitable membranes.

HTR1B - colon
HTR1B - cerebral cortex

KCNA5 - soft tissue
KCNA5 - heart muscle

Blood vessel function

The blood circulatory system consists of a network of blood vessels extending throughout the body, facilitating the transportation of various substances that are vital to normal bodily functions.These include oxygen, carbon dioxide, nutrients, hormones, immune cells, and other important molecules.

The endothelium, which lines the inside of the tube-like blood vessels, has diverse highly specialized roles. The cells in the endothelium transport molecules from the blood to the surrounding tissues using specialized organelles. In the capillaries of the brain, the cells express transport molecules that carry molecules across the blood brain barrier. In response to changes in the blood pressure, the cells in the endothelium secreted substances that affect the vascular smooth muscle, to either contract or dilate the blood vessels, depending on the blood pressure. The endothelial cells also control blood coagulation by producing factors that prevent blood clotting (under normal circumstances) and factors that activate blood clotting (in case of injury). In case of tissue damage or infection, endothelial cells also become activated and express cell adhesion molecules to facilitate the migration of circulating lymphocytes across the blood vessel and into the site of the tissue damage or infection.

Blood vessel histology

Oxygenated blood is trasnported from the heart through large arteries that gradually decrease in size and branch within the tissues to form arterioles. These arterioles open into a network of very fine blood vessels called capillaries. Deoxygenated blood travels from the capillary network toward the heart through small venules that eventually become larger veins.

Blood vessels are composed of three layers (tunica): intima, media, and adventitia. The inside of the tube-like blood vessel is lined with the tunica intima, which is composed of an endothelium made up of flattened epithelial cells. These cells lie on a basement membrane supported by a very thin subendothelial layer of fibrocollagenous tissue.

The tunica media is the middle layer and is composed mainly of smooth muscle reinforced by layers of elastic tissue. Elastic arteries, which are closest to the heart, have a media particularly rich in elastic tissue in order to adapt to the large pressure waves they receive. Elastic arteries gradually transform into muscular arteries farther from the heart, where the tunica media is dominated by smooth muscle. Muscular arteries are therefore highly contractile and regulate blood pressure by contracting or relaxing in response to vasoactive substances and signals from the autonomic nervous system.

The tunica adventitia is the outer layer of the blood vessel wall. It is mainly composed of collagen, though a few smooth muscle cells may also be present. In vessels with thick walls, adventitia also contains small blood vessels that supply the tunica media. The smooth muscle in the tunica media is innervated by autonomic nerves that run through the adventitia.

All blood vessels have a tunica intima, but smaller vessels progressively lose the tunica media and tunica adventitia. The media is much thicker in arteries than in veins of the same size, since blood pressure is relatively higher in arteries than in veins. In veins, the adventitia is often the predominant layer.

The histology of blood vessel including detailed images and information about the different cell types can be viewed in the Protein Atlas Histology Dictionary.

Background

Here, the protein-coding genes expressed in blood vessel are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize corresponding protein expression patterns of genes with elevated expression in blood vessel.

Transcript profiling was based on a combination of two transcriptomics datasets (HPA and GTEx, corresponding to a total of 14590 samples from 51 different human normal tissue types. The final consensus normalized expression (nTPM) value for each tissue type was used for the classification of all genes according to the tissue-specific expression into two different categories, based on specificity or distribution.

Relevant links and publications

Uhlén M et al., Tissue-based map of the human proteome. Science (2015)
PubMed: 25613900 DOI: 10.1126/science.1260419

Fagerberg L et al., Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. (2014)
PubMed: 24309898 DOI: 10.1074/mcp.M113.035600