Vascular smooth muscle cell (VSMC) hypertrophy is a characteristic feature of hypertensive vessels that contributes to abnormal vessel tone and structure. In intact aorta, the contractile agonist angiotensin II (ang II) regulates VSMC mass by stimulating an increase in protein synthesis. An in vitromodel of hypertrophy using cultured rat aortic VSMC is well defined, in which ang II induces a ~hypertrophic growth response~ consisting of an increase in protein synthesis and cell size without changes in DNA synthesis or cell number. There has been considerable interest in identifying the mechanisms and cellular signaling pathways whereby ang II stimulates VSMC hypertrophy. Previous work has shown that ang II activates a variety of second messengers, including Ca2+, protein kinase C (PKC), tyrosine kinases, and mitogen activated protein (MAP) kinases. MAP kinases are key mediators of cell growth and have been shown to regulate ribosomal kinases and initiation factors that are crucial for protein synthesis and hypertrophic and hyperplastic growth responses. Our preliminary data indicate that ang II causes a rapid Ca2+ dependent activation of MAP kinase in VSMC. Thus, the major hypothesis of this proposal is that Ca2+ -dependent Map kinase activation is a key mediator of ang II-induced VSMC hypertrophy. A series of experiments with a synthetic MEK inhibitor will determine whether inhibition of MAP kinases blocks rate limiting steps involved in VSMC protein synthesis and translation (as assessed by the regulation of the translation initiation factor eIF-4F) that are crucial to the ang II-induced hypertrophic growth response. A series of pharmacological, biochemical and molecular studies are designed to identify Ca2+ dependent components of the MAP kinase pathway (Shc, Ras, Raf) that are activated by ang II in VSMC. Finally, cellular mechanisms, by which Ca2+ regulates the MAP kinase pathway will be determined. These studies will concentrate on Ca2+ -dependent forms of PKC and calmodulin by use of pharmacological and antisense oligonucleotide inhibitors of PKC and calmodulin affinity chromatography. The proposed investigations are of fundamental importance and will critically test the major hypothesis. Future development of therapeutic strategies specifically targeted to signaling pathways involved in VSMC hypertrophy may have important clinical implications in the treatment of hypertension and atherosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
Application #
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Schools of Medicine
United States
Zip Code
Zhang, Xu; Wang, Qian; Gablaski, Brian et al. (2013) A microdevice for studying intercellular electromechanical transduction in adult cardiac myocytes. Lab Chip 13:3090-7
Trask, Aaron J; Katz, Paige S; Kelly, Amy P et al. (2012) Dynamic micro- and macrovascular remodeling in coronary circulation of obese Ossabaw pigs with metabolic syndrome. J Appl Physiol (1985) 113:1128-40
Olave, Nelida; Nicola, Teodora; Zhang, Wei et al. (2012) Transforming growth factor-? regulates endothelin-1 signaling in the newborn mouse lung during hypoxia exposure. Am J Physiol Lung Cell Mol Physiol 302:L857-65
Souza-Smith, Flavia M; Katz, Paige S; Trask, Aaron J et al. (2011) Mesenteric resistance arteries in type 2 diabetic db/db mice undergo outward remodeling. PLoS One 6:e23337
Nicola, Teodora; Ambalavanan, Namasivayam; Zhang, Wei et al. (2011) Hypoxia-induced inhibition of lung development is attenuated by the peroxisome proliferator-activated receptor-? agonist rosiglitazone. Am J Physiol Lung Cell Mol Physiol 301:L125-34
Hutchinson, Kirk R; Stewart Jr, James A; Lucchesi, Pamela A (2010) Extracellular matrix remodeling during the progression of volume overload-induced heart failure. J Mol Cell Cardiol 48:564-9
Nicola, Teodora; Hagood, James S; James, Masheika L et al. (2009) Loss of Thy-1 inhibits alveolar development in the newborn mouse lung. Am J Physiol Lung Cell Mol Physiol 296:L738-50
Byron, Kenneth L; Lucchesi, Pamela A (2002) Signal transduction of physiological concentrations of vasopressin in A7r5 vascular smooth muscle cells. A role for PYK2 and tyrosine phosphorylation of K+ channels in the stimulation of Ca2+ spiking. J Biol Chem 277:7298-307