Figure 2.

Proposed mechanism of local GPCR agonists in response to smooth muscle stretch. VSMC stretch activates the generation and release of several autacoids. (A) Phospholipase A₂ generates arachidonic acid (AA), which can be metabolized into thromboxane A₂ (TXA₂) and 20-hydroxyeicosatetraenoic acid (20-HETE) through the respective action of cyclooxygenase (COX) and cytochrome P450 (CYP) enzymes. 20-HETE inhibits calcium-activated potassium channels (BK_Ca), thus limiting VSMC hyperpolarization. Both TXA₂ and 20-HETE may act locally on an autocrine mode on VSMC TP receptor (TPR). (B) Sphingosine kinase-1 (SphK1) translocates to plasma membrane in response to stretch and phosphorylates sphingosine (Sph) to generate sphingosine-1-phosphate (S1P). This reaction is functionally antagonized by the sphingosine-1-phosphate specific phosphatase (SPP1). S1P activates S1P2 or 3 receptors (S1PR) to reinforce contraction. (C) Nucleotides are released in response to cell stretch,⁷² most probably through membrane hemichannels (HC). Autocrine activation of purinergic receptor (P2YR) by uridine-5′-tri and/or diphosphate (UTP, UDP) reinforces contraction. UTP receptor-dependent activation of TRPC3 channel further increases Ca²⁺ rise. This effect of extracellular nucleotides is controlled by CD39 ectonucleotidase.⁷⁰ (D) AngiotensinII type 1 receptor (AT1R) has been proposed to be directly activated by stretch and to subsequently activate TRPC6 channels.⁷⁸