Hypertension is a major public health issue impacting one in two adults in the United States and accounts for 10 million deaths each year worldwide. It is a leading risk factor for multiple diseases, including stroke, myocardial infarction, chronic kidney disease, and peripheral artery disease. The prevalence of hypertension increases with age in both sexes. In addition, aging is associated with significantly higher hypertension-related morbidity and mortality and insufficient control of high blood pressure. Critically, menopause is linked to a 2-fold increase in hypertension risk and premenopausal women have lower hypertension rates compared to men of similar age. Increased sympathetic nervous system activity, inflammation, and remodeling of large arteries like the aorta have been implicated in both normal aging and the pathophysiology of hypertension. Despite extensive hypertension research and the rapidly growing aging population, only 4% of hypertension studies focus on aging. Increased molecular insight into the mechanisms mediating arterial remodeling in age-dependent hypertension could uncover potential therapeutics for more targeted treatment of hypertension. In this thesis, Sprague Dawley rats were used in the models of normal aging and norepinephrine-induced hypertension to investigate the complex interplay between aging, sympathetic nervous system activity, and inflammation in arterial remodeling in age-dependent hypertension and potential sex differences. Our key findings from the abdominal aorta and renal artery are (1) Sex-dependent changes in the phosphorylation of c-Src kinase and ERK1/2, and expression of caveolin-1, (2) Altered expression of alpha-SMA and MHY-11, (3) Partial recapitulation of aged hypertensive phenotype in the abdominal aorta of young male rats following NE-infusion. Our proteomic and phosphoproteomic analyses of the aorta of young normotensive and aged hypertensive male rats have identified 58 differentially expressed proteins and 39 differentially phosphorylated proteins. Proteome analysis further revealed that the proteins in extracellular matrix, actin cytoskeleton and inflammatory pathways were the top affected proteins or pathways. Moreover, in phosphoproteome analysis, major differences were found in neurons, synapse structures, vascular smooth muscle cells, and focal adhesions. Notably, approximately two-thirds of differentially phosphorylated proteins (22 out of 39) were found to be at neurons and synapses. In the assessment of inflammatory mediators, we found that increases in multiple homeostatic cytokines including, CCL21, MMP2, and osteopontin were associated with the aortic remodeling in age-dependent hypertension. Collectively, these results support a model in which aging, increased sympathetic nervous system activity, and inflammation contribute to arterial remodeling in age-dependent hypertension. / 2024-11-02T00:00:00Z