Targeting sympathetic glia for treating cardiovascular diseases

Xie, Alison Xiaoqiao; Chaia, Angelo; McCarthy, Ken D.

doi:10.14800/rci.1572

Cited by 2 publications

(2 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, Gi-DREADD has been commonly used to inhibit neuronal activity and decrease signal transduction in neural circuits [ 78 ]. Gi-DREADD can be expressed transgenically [ 21 ] or with the help of viral vectors [ 79 ]. In this study, we demonstrated high tropism of Gi-DREADD expression in TRPV1-positive neurons in lumbosacral DRG, and in the dorsal horn of the spinal cord using TRPV1-Cre mice and hSyn promotors in AAV vectors.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacogenetic inhibition of lumbosacral sensory neurons alleviates visceral hypersensitivity in a mouse model of chronic pelvic pain

et al. 2022

View full text Add to dashboard Cite

The study investigated the cellular and molecular mechanisms in the peripheral nervous system (PNS) underlying the symptoms of urologic chronic pelvic pain syndrome (UCPPS) in mice. This work also aimed to test the feasibility of reversing peripheral sensitization in vivo in alleviating UCPPS symptoms. Intravesical instillation of vascular endothelial growth factor A (VEGFA) was used to induce UCPPS-like symptoms in mice. Spontaneous voiding spot assays and manual Von Frey tests were used to evaluate the severity of lower urinary tract symptoms (LUTS) and visceral hypersensitivity in VEGFA-instilled mice. Bladder smooth muscle strip contractility recordings (BSMSC) were used to identify the potential changes in myogenic and neurogenic detrusor muscle contractility at the tissue-level. Quantitative real-time PCR (qPCR) and fluorescent immunohistochemistry were performed to compare the expression levels of VEGF receptors and nociceptors in lumbosacral dorsal root ganglia (DRG) between VEGFA-instilled mice and saline-instilled controls. To manipulate primary afferent activity, Gi-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADD) were expressed in lumbosacral DRG neurons of TRPV1-Cre-ZGreen mice via targeted adeno-associated viral vector (AAVs) injections. A small molecule agonist of Gi-DREADD, clozapine-N-oxide (CNO), was injected into the peritoneum (i. p.) in awake animals to silence TRPV1 expressing sensory neurons in vivo during physiological and behavioral recordings of bladder function. Intravesical instillation of VEGFA in the urinary bladders increased visceral mechanical sensitivity and enhanced RTX-sensitive detrusor contractility. Sex differences were identified in the baseline detrusor contractility responses and VEGF-induced visceral hypersensitivity. VEGFA instillations in the urinary bladder led to significant increases in the mRNA and protein expression of transient receptor potential cation channel subfamily A member 1 (TRPA1) in lumbosacral DRG, whereas the expression levels of transient receptor potential cation channel subfamily V member 1 (TRPV1) and VEGF receptors (VEGFR1 and VEGFR2) remained unchanged when compared to saline-instilled animals. Importantly, the VEGFA-induced visceral hypersensitivity was reversed by Gi-DREADD-mediated neuronal silencing in lumbosacral sensory neurons. Activation of bladder VEGF signaling causes sensory neural plasticity and visceral hypersensitivity in mice, confirming its role of an UCPPS biomarker as identified by the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research studies. Pharmacogenetic inhibition of lumbosacral sensory neurons in vivo completely reversed VEGFA-induced pelvic hypersensitivity in mice, suggesting the strong therapeutic potential for decreasing primary afferent activity in the treatment of pain severity in UCPPS patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Manipulation Of Sensory Neuronal Signaling To Improve Bladder Sensitivitymentioning

confidence: 99%

Pharmacogenetic inhibition of lumbosacral sensory neurons alleviates visceral hypersensitivity in a mouse model of chronic pelvic pain

et al. 2022

View full text Add to dashboard Cite

show abstract

Glial cell activity in cardiovascular diseases and risk of acute myocardial infarction

Truter

Malan

Essop

2023

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Growing evidence indicates that the pathophysiological link between the brain and heart underlies cardiovascular diseases, specifically acute myocardial infarction (AMI). Astrocytes are the most abundant glial cells in the central nervous system and provide support/protection for neurons. Astrocytes and peripheral glial cells are emerging as key modulators of the brain-heart axis in AMI, by affecting sympathetic nervous system activity (centrally and peripherally). This review therefore aimed to gain an improved understanding of glial cell activity and AMI risk. This includes discussions on the potential role for contributing factors in AMI risk, i.e., autonomic nervous system dysfunction, glial-neurotrophic and ischemic risk markers (glial cell line-derived neurotrophic factor [GDNF], astrocytic S100 calcium-binding protein B [S100B], silent myocardial ischemia, and cardiac troponin T [cTnT]). Consideration of glial cell activity and related contributing factors in certain brain-heart disorders namely blood-brain barrier dysfunction, myocardial ischemia, and chronic psychological stress, may improve our understanding regarding the pathological role that glial dysfunction can play in the development/onset of AMI. Here, findings demonstrated perturbations in glial cell activity and contributing factors (especially sympathetic activity). Moreover, emerging AMI risk included sympatho-vagal imbalance, low GDNF levels reflecting prothrombic risk, hypertension, and increased ischemia due to perfusion deficits (indicated by S100B and cTnT levels). Such perturbations impacted blood-barrier function and perfusion which were exacerbated during psychological stress. Thus, greater insights and consideration regarding such biomarkers may help drive future studies investigating brain-heart axis pathologies to gain a deeper understanding of astrocytic glial cell contributions and unlock potential novel therapies for AMI.

show abstract

Targeting sympathetic glia for treating cardiovascular diseases

Cited by 2 publications

References 46 publications

Pharmacogenetic inhibition of lumbosacral sensory neurons alleviates visceral hypersensitivity in a mouse model of chronic pelvic pain

Pharmacogenetic inhibition of lumbosacral sensory neurons alleviates visceral hypersensitivity in a mouse model of chronic pelvic pain

Glial cell activity in cardiovascular diseases and risk of acute myocardial infarction

Contact Info

Product

Resources

About