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Smooth Muscle Cells: Researching New Therapies for Bladder Disorders

Bladder Anatomy and Function

The bladder is responsible for collecting and storing the urine produced by the kidneys until it is voided from the body during urination. The inner epithelial layer of the bladder is called the urothelium and is a type of stratified epithelium that contracts and expands with the organ. The bladder wall is composed of smooth muscle cells, which drive this contraction and relaxation and in turn, regulate urination. Bladder smooth muscle activity is also controlled by nervous system innervation, which relay to the brain when the bladder is full and mediate bladder emptying. Importantly, dysfunction of the neuronal components that regulate the bladder, or dysfunction of the bladder itself, can lead to lower urinary tract symptoms including an overactive bladder or incontinence.

Recent Research Using Lifeline® Bladder Smooth Muscle Cells

Lower urinary tract symptoms are a group of conditions common in adults over the age of 40. Although drugs treating LUTS are available, there is an unmet clinical need for new therapies with better efficacy and improved safety profiles. Contraction of the bladder smooth muscle for urination is regulated by parasympathetic neurons, which release acetylcholine and ATP. ATP binds the purinergic receptor P2X1 to exert its effects, and its metabolite, ADP, binds to the P2Y12 receptor, which was previously shown to regulate ADP-mediated bladder contraction. However, the role of purinergic signaling in human bladder function is debated. In a study from 2019, Hao and colleagues set out to further define the importance of purinergic signaling in the bladder.

First, using strips of bladder smooth muscle isolated from the mouse, the researchers began to investigate the mechanisms of bladder smooth muscle physiology by parsing out the pathways required for bladder smooth muscle cell relaxation. They found that treatment of bladder smooth muscle with NECA (an adenosine agonist that activates A2 receptors) blocked purinergic contraction. Using A2 receptor agonists against A2a and A2b, the group found that Bay 60-6583 (A2b agonist) had a greater inhibitory effect, suggesting that A2b is the predominant A2 receptor that blocks purinergic contraction in the bladder smooth muscle; these results were also validated in A2b-knockout mice.

Next, the researchers used knockout mouse models lacking either the A2b or P2Y12 receptors to determine how they regulate bladder function. Interestingly, they found that loss of either of these receptors had an opposite effect as the other. Mice lacking P2Y12 had an underactive bladder with larger capacity, decreased voiding frequency, and longer voiding intervals. In contrast, mice lacking A2b had an overactive bladder with reduced capacity, increased voiding frequency, and shorter voiding intervals. These opposing phenotypes were also observed when bladder smooth muscle contraction force was measured: mice lacking P2Y12 exhibited stronger contractile force, while mice lacking A2b exhibited weaker contractile force.

To translate their results to human cells, the authors used Lifeline® human bladder smooth muscle cells to confirm that downstream calcium signaling modulates purinergic contractility in response to AC-cAMP. Consistent with their findings in mouse bladder smooth muscle cells, the group found that ATP and ADPbS stimulate calcium influx, which was sensitive to inhibition by A2b signaling.

To further understand the different effects on bladder size, the group analyzed bladder smooth muscle cell growth in mice lacking A2b or P2Y12. Their results demonstrated that loss of A2b resulted in smaller muscle cells, while the loss of P2Y12 resulted in larger muscle cells. Finally, the group hypothesized that treatment with P2Y12 or A2b antagonists might rescue the bladder phenotype observed in mice lacking the other receptor. They found that this was in fact true: in mice lacking P2Y12 and treated with an A2b receptor antagonist (PSB1115), the underactive bladder phenotype was improved. Similarly, in mice lacking A2b and treated with a P2Y12 antagonist (Ticagrelor), the overactive bladder phenotype was rescued.

Together, the results of this study demonstrate an intricate interplay between P2Y12 and A2b receptors in the bladder smooth muscle and illustrate that PSB1115 and Ticagrelor are potential drug candidates for treating patients with lower urinary tract symptoms.

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