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Role of NCK2 Signaling and Mechanical Forces in Endothelial Dysfunction and Atherosclerosis
Abstract
A better understanding of endothelial dysfunction holds promise for more effective interventions for atherosclerosis prevention and treatment. Endothelial dysfunction resulting from metabolic imbalance in combination with abnormal mechanotransduction drives atherosclerosis. Current therapies for atherosclerosis rely on reducing cholesterol and inflammation but do not preserve or restore endothelial homeostasis. Development of improved therapies requires, therefore, a better understanding of mechanisms underpinning endothelial dysfunction. To bridge this gap in knowledge, we examined key pathways modulating the endothelial and arterial phenotype in proatherogenic mouse models.
Our first study explored endothelial signaling by the non-catalytic region of the tyrosine kinase (NCK) family of adaptors, consisting of NCK1 and NCK2, which are involved in cardiovascular development and postnatal angiogenesis. We showed stage- and sex-dependent effects of endothelial NCK2 signaling on arterial wall inflammation and atherosclerosis development. Male and female Nck1-null atheroprone (APOE-deficient) mice enabling inducible, endothelial-specific Nck2 inactivation were fed a high fat diet for 8 or 16 weeks to model atherosclerosis initiation and progression, respectively. At advanced stages of disease, plaque size and severity of atherosclerotic lesions were reduced, only in males, by abrogation of endothelial NCK2 signaling. Markers of vascular inflammation were reduced by endothelial NCK2 deficiency in both males and females during atherosclerosis progression. Collectively, these results demonstrate stage- and sex-dependent modulation of atherosclerosis development by endothelial NCK2 signaling.
Our second study aimed to decouple the effect of disturbed blood flow from arterial wall stiffening in the endothelial mechanical phenotype. We induced acute or chronic disturbed blood flow via partial ligation (PCL) of the left carotid in male and female mice. To modulate arterial wall stiffness, mice experiencing chronic disturbed blood flow were also affixed with osmotic minipumps delivering saline or 150 mg/kg/day of β-aminopropionitrile (BAPN), an inhibitor of the collagen crosslinking enzymes of the lysyl oxidase family. Two days (acute) or two weeks (chronic) after induction of disturbed blood flow by PCL, we determined the elastic moduli of the endothelium and subendothelial matrix of carotid preparations en face using atomic force microscopy. We found that preventing stiffening of the arterial wall by BAPN treatment increases endothelial and subendothelial compliance, a finding with potential therapeutic implications in atherosclerosis.
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Citation
Bywaters, Briana Christine (2023). Role of NCK2 Signaling and Mechanical Forces in Endothelial Dysfunction and Atherosclerosis. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /202811.