Vascular smooth muscle ROCK1 contributes to hypoxia-induced pulmonary hypertension development in mice

Penumatsa, Krishna; Singhal, A.; Warburton, Rod R.; Bear, Michael; Bhedi, Chinmayee D.; Nasirova, Sabina; Wilson, Jenna; Qi, Guanming; Preston, Ioana R.; Hill, Nicholas S.; Fanburg, Barry L.; Kim, Young–Bum; Toksoz, Deniz

doi:10.1016/j.bbrc.2022.02.064

Cited by 3 publications

(1 citation statement)

References 28 publications

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“…Rho kinases belong to the serine/threonine kinase family, and the serine/threonine kinase Rho kinase (ROCK) mediates a variety of cellular responses related to PAH [ 107 ]. Rho kinase causes excessive vascular smooth muscle contraction and vascular remodeling through inhibition of myosin phosphatase and activation of its downstream effectors [ 108 ].…”

Section: Transcription Factors Are Involved In Hypoxia-induced Vascul...mentioning

confidence: 99%

Mechanism of Hypoxia-Mediated Smooth Muscle Cell Proliferation Leading to Vascular Remodeling

Huang

Akgün

Mehmood

et al. 2022

BioMed Research International

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Vascular remodeling refers to changes in the size, contraction, distribution, and flow rate of blood vessels and even changes in vascular function. Vascular remodeling can cause cardiovascular and cerebrovascular diseases. It can also lead to other systemic diseases, such as pulmonary hypertension, pulmonary atherosclerosis, chronic obstructive pulmonary disease, stroke, and ascites of broilers. Hypoxia is one of the main causes of vascular remodeling. Prolonged hypoxia or intermittent hypoxia can lead to loss of lung ventilation, causing respiratory depression, irregular respiratory rhythms, and central respiratory failure. Animals that are unable to adapt to the highland environment are also prone to sustained constriction of the small pulmonary arteries, increased resistance to pulmonary circulation, and impaired blood circulation, leading to pulmonary hypertension and right heart failure if they live in a highland environment for long periods of time. However, limited studies have been found on the relationship between hypoxia and vascular remodeling. Therefore, this review will explore the relationship between hypoxia and vascular remodeling from the aspects of endoplasmic reticulum stress, mitochondrial dysfunction, abnormal calcium channel, disordered cellular metabolism, abnormal expression of miRNA, and other factors. This will help to understand the detailed mechanism of hypoxia-mediated smooth muscle cell proliferation and vascular remodeling for the better treatment and management of diseases due to vascular remodeling.

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Section: Transcription Factors Are Involved In Hypoxia-induced Vascul...mentioning

confidence: 99%

Mechanism of Hypoxia-Mediated Smooth Muscle Cell Proliferation Leading to Vascular Remodeling

Huang

Akgün

Mehmood

et al. 2022

BioMed Research International

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Endothelial Rho kinase controls blood vessel integrity and angiogenesis

Lange,

Francis,

Furtado

et al. 2024

Preprint

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Background: The Rho kinases 1 and 2 (ROCK1/2) are serine-threonine specific protein kinases that control actin cytoskeleton dynamics. They are expressed in all cells throughout the body, including cardiomyocytes, smooth muscle cells and endothelial cells, and intimately involved in cardiovascular health and disease. Pharmacological ROCK inhibition is beneficial in mouse models of hypertension, atherosclerosis, and neointimal thickening that display overactivated ROCK. However, the consequences of endothelial ROCK signaling deficiency in vivo remain unknown. To address this issue, we analyzed endothelial cell (EC) specific ROCK1 and 2 deletions. Methods: We generated Cdh5-CreERT2 driven, tamoxifen inducible loss of function alleles of ROCK1 and ROCK2 and analyzed mouse survival and vascular defects through cellular, biochemical, and molecular biology approaches. Results: We observed that postnatal or adult loss of endothelial ROCK1 and 2 was lethal within a week. Mice succumbed to multi-organ hemorrhage that occurred because of loss of vascular integrity. ECs displayed deficient cytoskeletal actin polymerization that prevented focal adhesion formation and disrupted junctional integrity. Retinal sprouting angiogenesis was also perturbed, as sprouting vessels exhibited lack of polymerized actin and defective lumen formation. In a three-dimensional endothelial sprouting assay, combined knockdown of ROCK1/2 or knockdown or ROCK2 but not ROCK1 led to reduced sprouting, lumenization and cell polarization defects caused by defective actin and altered VE-cadherin dynamics. The isoform specific role of endothelial ROCK2 correlated with ROCK2 substrate specificity for FAK and LIMK. By analyzing single and three allele mutants we show that one intact allele of ROCK2 is sufficient to maintain vascular integrity in vivo. Conclusion: Endothelial ROCK1 and 2 maintain junctional integrity and ensure proper angiogenesis and lumen formation. The presence of one allele of ROCK2 is sufficient to maintain vascular growth and integrity. These data indicate the need of careful consideration for the use of ROCK inhibitors in disease settings.

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Role of KCNK3 Dysfunction in Dasatinib-associated Pulmonary Arterial Hypertension and Endothelial Cell Dysfunction

Ribeuz,

Willer,

Chevalier

et al. 2024

Am J Respir Cell Mol Biol

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Vascular smooth muscle ROCK1 contributes to hypoxia-induced pulmonary hypertension development in mice

Cited by 3 publications

References 28 publications

Mechanism of Hypoxia-Mediated Smooth Muscle Cell Proliferation Leading to Vascular Remodeling

Mechanism of Hypoxia-Mediated Smooth Muscle Cell Proliferation Leading to Vascular Remodeling

Endothelial Rho kinase controls blood vessel integrity and angiogenesis

Role of KCNK3 Dysfunction in Dasatinib-associated Pulmonary Arterial Hypertension and Endothelial Cell Dysfunction

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