Significance: The endothelium regulates vessel dilation and constriction, balances hemostasis, and inhibits thrombosis. In addition, pro- and 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. 22, 1212-1229.