Vascular smooth muscle phenotypic diversity and function

Abstract

The control of force production in vascular smooth muscle is critical to the normal regulation of blood flow and pressure, and altered regulation is common to diseases such as hypertension, heart failure, and ischemia. A great deal has been learned about imbalances in vasoconstrictor and vasodilator signals, e.g., angiotensin, endothelin, norepinephrine, and nitric oxide, that regulate vascular tone in normal and disease contexts. In contrast there has been limited study of how the phenotypic state of the vascular smooth muscle cell may influence the contractile response to these signaling pathways dependent upon the developmental, tissue-specific (vascular bed) or disease context. Smooth, skeletal, and cardiac muscle lineages are traditionally classified into fast or slow sublineages based on rates of contraction and relaxation, recognizing that this simple dichotomy vastly underrepresents muscle phenotypic diversity. A great deal has been learned about developmental specification of the striated muscle sublineages and their phenotypic interconversions in the mature animal under the control of mechanical load, neural input, and hormones. In contrast there has been relatively limited study of smooth muscle contractile phenotypic diversity. This is surprising given the number of diseases in which smooth muscle contractile dysfunction plays a key role. This review focuses on smooth muscle contractile phenotypic diversity in the vascular system, how it is generated, and how it may determine vascular function in developmental and disease contexts.

Fig. 1.

Control of gene expression, vascular smooth muscle contraction, and functional diversity. A: different sets of genes are transcribed in phasic vs. tonic smooth muscle. Genes are specifically transcribed in slow (striated) muscle under the control of nuclear factor of activated T cells (NFAT) and peroxisome-proliferator-activated receptor (PPAR). Diversity is also generated by multiple transcription start sites within each gene. B: additional diversity is generated by the alternative splicing of exons (filled box); only one of many types of alternative splicing is shown. In limited studies TIA proteins are proposed to mediate slow splicing and Tra proteins fast splicing, while other factors that may play a role in tissue-specific splicing of exons have not been studied in this context. microRNAs (miR143, 145) regulate gene expression by binding to 3′-untranslated region and destabilizing the message or blocking its translation. C: the basic components of the contractile apparatus are depicted. Myosin binding to actin generates force and displacement. Myosin is activated by phosphorylation by myosin light chain kinase (MLCK) and deactivated by dephosphorylation by myosin light-chain phosphatase (MLCP aka myosin phosphatase or MP). MLCK activity is regulated by calcium, while MLCP is both positively and negatively regulated by a number of signaling pathways. D: smooth muscle may produce force in a tonic or phasic pattern. In the vasculature phasic force production is termed vasomotion. Abbreviations are defined in the text.

Fig. 2.

MP isoforms. A 31 nt exon near the 3′ end of the gene is skipped in tonic and included in phasic smooth muscle. Skipping of the alternative exon codes for a COOH-terminal leucine zipper motif (LZ+) that mediates the heterodimerization of cGMP kinase (cGK1α) with MYPT1. This dimerization is proposed to be required for cGMP activation of myosin phosphatase (MP) and calcium desensitization of force production. Inclusion of the 31 nt exon in phasic smooth muscle codes for the LZ− isoform, which does not dimerize with cGK and thus cGMP does not activate MP.

Fig. 3.

The vascular system and inputs that may control smooth muscle diversity. A: the vascular system may be categorized as pulmonic vs. systemic and macro- vs. microvascular. The large arteries and veins, e.g., aorta and inferior vena cava, contain smooth muscle of a pure tonic phenotype. The systemic microvascular (resistance artery) smooth muscle exhibits a mixed phasic/tonic phenotype. B: inputs that may control vascular smooth muscle phenotype include neural input, mechanical load, which is a function of pressure (stress/strain) and flow (shear), and local and distant hormonal signals.