Critical Regulators of Endothelial Cell Functions : For a Change Being Alternative

Significance: The endothelium regulates vessel dilation and constriction, balances hemostasis, and inhibits thrombosis. In addition, proand anti-angiogenic molecules orchestrate proliferation, survival, and migration of endothelial cells. Regulation of all these processes requires fine-tuning of signaling pathways, which can easily be tricked into running the opposite direction when exogenous or endogenous signals get out of hand. Surprisingly, some critical regulators of physiological endothelial functions can turn malicious by mere alternative splicing, leading to the expression of protein isoforms with opposite functions. Recent Advances: While reviewing the evidence of alternative splicing on cellular physiology, it became evident that expression of splice factors and their activities are regulated by externally triggered signaling cascades. Furthermore, genome-wide identification of RNA-binding sites of splicing regulatory proteins now offer a glimpse into the splicing code responsible for alternative splicing of molecules regulating endothelial functions. Critical Issues: Due to the constantly growing number of transcript and protein isoforms, it will become more and more important to identify and characterize all transcripts and proteins regulating endothelial cell functions. One critical issue will be a non-ambiguous nomenclature to keep consistency throughout different laboratories. Future Directions: RNA-deep sequencing focusing on exon–exon junction needs to more reliably identify alternative splicing events combined with functional analyses that will uncover more splice variants contributing to or inhibiting proper endothelial functions. In addition, understanding the signals mediating alternative splicing and its regulation might allow us to derive new strategies to preserve endothelial function by suppressing or upregulating specific protein isoforms. Antioxid. Redox Signal. 00, 000–000. Endothelium—Function and Dysfunction The cardiovascular system composed of heart and blood vessels transports blood through the organism to deliver oxygen and nutrients to all organs as well as carbon dioxide and metabolic end products to the lungs and excretory organs for exhalation and disposal. The border between the blood stream and the surrounding tissues is the vessel wall, which—in all larger vessels—principally consists of three layers (Fig. 1). The outer layer or adventitia is entirely composed of connective tissue containing elastic and collagen fibers synthesized by fibroblasts. It is followed by the media, which is made up of vascular smooth muscle cells required for vasoconstriction and -dilation; in veins, the media is much thinner than in arteries. Both these layers are not present in capillaries, the smallest of the body’s blood vessels. The innermost layer, the intima, is separated from the media by an elastic membrane, the elastica interna. It consists of a monolayer of endothelial cells, which are directly at the interface with the blood stream. The endothelium plays a key role in many physiological processes such as regulation of vascular tone, hemostasis, thrombosis, and angiogenesis. For a long time, it was assumed that the endothelium mainly represents an inert barrier, which simply separates Heisenberg-Group—Environmentally-Induced Cardiovascular Degeneration, IUF—Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany. Institute for Virology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. Central Institute of Clinical Chemistry and Laboratory Medicine, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany. *These two authors contributed equally to the work. Shared senior authors. ANTIOXIDANTS & REDOX SIGNALING Volume 00, Number 00, 2014 a Mary Ann Liebert, Inc. DOI: 10.1089/ars.2014. 6023