The traditional view has been that hypoxic growth of pulmonary artery (PA) smooth muscle cells (SMC) in chronic pulmonary hypertension is a direct consequence of sustained vasoconstriction and resulting mechanical stress, endothelial injury, and local growth factor production. Although hypoxia is not generally thought to directly promote proliferation of PA SMC, we have discovered a unique synergistic mechanism by which hypoxia can directly augment and sustain proliferative signals in the vessel wall. Following """"""""priming"""""""" with mechanical stress or peptide mitogens, PA SMC acquire the ability to proliferate in response to hypoxia. We now have evidence that there is heterogeneity in the proliferative response of PA SMC subpopulations to hypoxia and that the magnitude of their hypoxic growth is enhanced following vascular injury. However, the mechanisms that regulate the expression of this hypoxia-sensitive phenotype in PA, SMC and permit this novel form of proliferative synergy to occur are not understood. We have generated data that suggests that activation of the calcium dependent alpha isoform of protein kinase C (PKC)--an important proliferative kinases--is uniquely important in the initiation of this hypoxic growth. However, the role that PKC-alpha activation plays in regulating the magnitude of hypoxic proliferation is not clear. Many of the mechanisms that regulate PKC-alpha activation are not well understood. We also have data suggesting a direct link between increased expression of PKC-alpha activation are not well understood. We also have data suggesting a direct link between increased expression of PKC-alpha and augmented hypoxic growth may exist. The mechanisms that regulate the expression and degradation of PKC-alpha are not known. Therefore, the overall goal of this proposal is to determine if PKC-alpha activation and expression control PA SMC hypoxic growth and to elucidate mechanisms that regulate activation and expression of PKC-alpha in these cells.
The specific aims will test the central hypothesis that: Activation and expression of PKC- alpha are critical determinants of PA SMC proliferative response to hypoxia in vivo and in vitro. This project should increase our understanding of the mechanisms that control synergy, heterogeneity, and injury-induced upregulation in hypoxic growth of PA SMC in chronic pulmonary hypertension. It will also generate useful new information on the basic biology of PKC. Several emerging concepts in signal transduction will be addressed including the importance of heterogeneity within kinase families, phosphatases and intracellular protease in the regulation of kinase activity and expression, modulation of kinase gene expression by extracellular stimuli, cross talk within and between kinase cascades, and interaction between upstream kinases and selected cell cycle intermediates and transcription factors.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
United States
Zip Code
Jiang, Xinguo; Nicolls, Mark R; Tian, Wen et al. (2018) Lymphatic Dysfunction, Leukotrienes, and Lymphedema. Annu Rev Physiol 80:49-70
Schäfer, Michal; Humphries, Stephen; Stenmark, Kurt R et al. (2018) 4D-flow cardiac magnetic resonance-derived vorticity is sensitive marker of left ventricular diastolic dysfunction in patients with mild-to-moderate chronic obstructive pulmonary disease. Eur Heart J Cardiovasc Imaging 19:415-424
D'Alessandro, Angelo; El Kasmi, Karim C; Plecitá-Hlavatá, Lydie et al. (2018) Hallmarks of Pulmonary Hypertension: Mesenchymal and Inflammatory Cell Metabolic Reprogramming. Antioxid Redox Signal 28:230-250
Karoor, Vijaya; Fini, Mehdi A; Loomis, Zoe et al. (2018) Sustained Activation of Rho GTPases Promotes a Synthetic Pulmonary Artery Smooth Muscle Cell Phenotype in Neprilysin Null Mice. Arterioscler Thromb Vasc Biol 38:154-163
Stenmark, Kurt R; Graham, Brian B (2018) Urocortin 2: will a drug targeting both the vasculature and the right ventricle be the future of pulmonary hypertension therapy? Cardiovasc Res 114:1057-1059
Madhavan, Krishna; Frid, Maria G; Hunter, Kendall et al. (2018) Development of an electrospun biomimetic polyurea scaffold suitable for vascular grafting. J Biomed Mater Res B Appl Biomater 106:278-290
Stenmark, Kurt R; Frid, Maria G; Graham, Brian B et al. (2018) Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension. Cardiovasc Res 114:551-564
Schäfer, Michal; Kheyfets, Vitaly O; Barker, Alex J et al. (2018) Reduced shear stress and associated aortic deformation in the thoracic aorta of patients with chronic obstructive pulmonary disease. J Vasc Surg 68:246-253
Graham, Brian B; Kumar, Rahul; Mickael, Claudia et al. (2018) Vascular Adaptation of the Right Ventricle in Experimental Pulmonary Hypertension. Am J Respir Cell Mol Biol 59:479-489
Wick, Marilee J; Harral, Julie W; Loomis, Zoe L et al. (2018) An Optimized Evans Blue Protocol to Assess Vascular Leak in the Mouse. J Vis Exp :

Showing the most recent 10 out of 148 publications