The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

The detrusor smooth muscle is the main muscle component of the urinary bladder wall. Its ability to contract over a large length interval and to relax determines the bladder function during filling and micturition. These processes are regulated by several external nervous and hormonal control systems, and the detrusor contains multiple receptors and signaling pathways. Functional changes of the detrusor can be found in several clinically important conditions, e.g., lower urinary tract symptoms (LUTS) and bladder outlet obstruction. The aim of this review is to summarize and synthesize basic information and recent advances in the understanding of the properties of the detrusor smooth muscle, its contractile system, cellular signaling, membrane properties, and cellular receptors. Alterations in these systems in pathological conditions of the bladder wall are described, and some areas for future research are suggested.

https://www.physiology.org/doi/pdf/10.1152/physrev.00038.2003

Urinary bladder contraction and relaxation: Physiology and pathophysiology

Botulinum-a toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? preliminary results

This article focuses on the regional heterogeneity of the mammalian sinoatrial (SA) node in terms of cell morphology, pacemaker activity, action potential configuration and conduction, densities of ionic currents (i(Na), i(Ca,L), i(to), i(K,r), i(K,s) and i(f)), expression of gap junction proteins (Cx40, Cx43 and Cx45), autonomic regulation, and ageing. Experimental studies on the single SA node cell to the whole animal are reviewed. The heterogeneity is considered in terms of the gradient model of the SA node, in which there is gradual change in the intrinsic properties of SA node cells from periphery to centre, and the alternative mosaic model, in which there is a variable mix of atrial and SA node cells from periphery to centre. The heterogeneity is important for the dependable functioning of the SA node as the pacemaker for the heart, because (i) via multiple mechanisms, it allows the SA node to drive the surrounding atrial muscle without being suppressed electrotonically; (ii) via an action potential duration gradient and a conduction block zone, it promotes antegrade propagation of excitation from the SA node to the right atrium and prevents reentry of excitation; and (iii) via pacemaker shift, it allows pacemaking to continue under diverse pathophysiological circumstances.

The sinoatrial node, a heterogeneous pacemaker structure.

1The responses of rabbit urinary bladder to hydrostatic pressure changes and to electrical stimulation have been investigated using both the Ussing chamber and a superfusion apparatus. These experiments enabled us to monitor changes in both ionic transport across the tissue and cellular ATP release from it.
2The urinary bladder of the rabbit maintains an electrical potential difference across its wall as a result largely of active sodium transport from the urinary (mucosal) to the serosal surface.
3Small hydrostatic pressure differences produced by removal of bathing fluid from one side of the tissue caused reproducible changes in both potential difference and short-circuit current. The magnitude of these changes increases as the volume of fluid removed increases.
3Amiloride on the mucosal (urinary), but not the serosal, surface of the membrane reduces the transepithelial potential difference and short-circuit current with an IC50 of 300 nm. Amiloride reduces the size of, but does not abolish, transepithelial potential changes caused by alterations in hydrostatic pressure.
4Field electrical stimulation of strips of bladder tissue produces a reproducible release of ATP. Such release was demonstrated to occur largely from urothelial cells and is apparently non-vesicular as it increases in the absence of calcium and is not abolished by tetrodotoxin.
5It is proposed that ATP is released from the urothelium as a sensory mediator for the degree of distension of the rabbit urinary bladder and other sensory modalities.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-7793.1997.503bb.x

ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes–possible sensory mechanism?

Specimens from the human male and female external urethral sphincter and the periurethral levator ani muscle have been examined using histochemical and electron microscopic techniques. In both sexes the external sphincter consists of a single population of type I (slow twitch) fibres with a mean diameter of 17.47 +/- 0.7 micrometers in the absence of muscle spindles. In contrast, the periurethral levator ani possesses muscle spindles and the constituent fibres form a heterogeneous population of type I and type II (fast twitch) fibres, with mean diameters of 45.5 +/- 0.8 micrometer and 59.5 +/- 3.4 micrometers respectively. These findings indicate that the external urethral sphincter is functionally adapted to maintain tone over prolonged periods and may be of considerable importance in producing active urethral closure during continence. The anatomical location and fibre characteristics of the levator ani muscle suggest that these fibres actively assist in urethral closure, particularly during events which cause elevation of intra-abdominal pressure. In view of the differences in fibre characteristics between the external urethral sphincter and the levator ani, EMG activity recorded from a single site in the levator ani may not be representative of the functional status either of other levator ani muscle fibres or of the external urethral sphincter.

John A. Gosling

Papers

A Comparative Study of the Human External Sphincter and Periurethral Levator Ani Muscles

Bladder Outflow Obstruction—A Cause of Denervation Supersensitivity

Obstructive response of human bladder to BPH vs. rabbit bladder response to partial outlet obstruction: a direct comparison.

Decrease in the autonomic innervation of human detrusor muscle in outflow obstruction.

The Autonomic Innervation of the Human Male and Female Bladder Neck and Proximal Urethra