TRP Channels in Angiogenesis and Other Endothelial Functions

Abstract

Angiogenesis is the growth of blood vessels mediated by proliferation, migration, and spatial organization of endothelial cells. This mechanism is regulated by a balance between stimulatory and inhibitory factors. Proangiogenic factors include a variety of VEGF family members, while thrombospondin and endostatin, among others, have been reported as suppressors of angiogenesis. Transient receptor potential (TRP) channels belong to a superfamily of cation-permeable channels that play a relevant role in a number of cellular functions mostly derived from their influence in intracellular Ca²⁺ homeostasis. Endothelial cells express a variety of TRP channels, including members of the TRPC, TRPV, TRPP, TRPA, and TRPM families, which play a relevant role in a number of functions, including endothelium-induced vasodilation, vascular permeability as well as sensing hemodynamic and chemical changes. Furthermore, TRP channels have been reported to play an important role in angiogenesis. This review summarizes the current knowledge and limitations concerning the involvement of particular TRP channels in growth factor-induced angiogenesis.

Keywords: TRP channels; TRPC; TRPM; TRPV; VEGF; angiogenesis; endothelial cells.

Figure 1

Schematic representation of various pathways activated by the VEGF-family members. By binding to their receptors (VEGFR1-3), indicated VEGF members activate several intracellular pathways involved in a range of cellular functions leading to angiogenesis and lymphangiogenesis.

Figure 2

Molecular structure and function of TRP channels. (A) Schematic representation of TRPC1 depicting functionally relevant domains. The cytoplasmic N- and C-termini of each TRP family contain different structural and functional domains as indicated. (B) Cartoon representing the topology of a TRP monomer within the plasma membrane, activation and functions associated to TRP channels in endothelial cells. The protein exhibits six transmembrane domains (TM1-TM6) with the pore located between transmembrane domains 5 and 6, and both N-terminal and C-terminal domains located in the cytosol. Endothelial TRP channels can be activated by receptor occupation, which, in turn, leads to the activation of phospholipase C and the generation of DAG and inositol 1,4,5-trisphosphate (IP₃). DAG is an endogenous activator of certain TRP channels and Ca²⁺ store depletion results in STIM1-dependent activation of TRPC1. Furthermore, TRP channels in endothelial cells can be activated by shear stress and the different EETs or their expression can be upregulated by hypoxia. Calcium influx via TRP channels is involved in Ca²⁺ store refilling, activation of Ca²⁺-binding proteins (CBP), cytoskeletal remodeling and the regulation of vascular permeability as well as the exocytosis of smooth muscle cell relaxing factors.