|Metabolism and Blood Vessels
The lab focuses on cardiovascular metabolism. The heart and skeletal muscle are highly metabolically active tissues. Their rates of energy consumption, choice of substrates, and method of catabolism can vary widely. Aberrant generation or use of energy in these tissues can lead to various diseases, including myopathies, heart failure, and diabetes. Conversely, optimal handling of energy improves exercise performance, and has beneficial impact on numerous chronic diseases, and aging itself.
Energy equivalents in the cell are most efficiently generated by complete oxidation, in the mitochondria, of substrates like sugars and fat. ATP is abundantly generated in the process, while free oxygen is obligatorily reduced to water. The generation and regulation of mitochondria is complex and highly regulated. Importantly, the proper delivery of oxygen and nutrients must also be closely coordinated with mitochondrial function. Highly oxidative tissues are thus invariably also highly vascular. The regulatory networks underlying these processes are only beginning to be understood.
Transcriptional co-activators are proteins that interact with DNA-bound transcription factors to regulate gene expression. It is likely that most if not all transcription factors require co-activators. Certain co-activators are highly regulated and integrate extracellular cues to affect gene regulation. Probably the best example of this is the small family of PGC-1 co-activators (PGC-1α, PGC-1β, and PRC). The PGC-1’s interact with a number of chromatin-bound transcription factors, including most nuclear receptors. The PGC-1’s assist in the activation of the basal transcriptional machinery, including the mediator complex; assist in the recruitment of chromatin-modifying enzymes such as histone acetylases like p300; and help coordinate transcription with the splicing machinery. The result is robust gene induction.
The PGC-1s control various biological pathways in different tissues. Common to these functions is the regulation of mitochondrial biogenesis and activity. The exogenous addition of PGC-1s is sufficient to drive the formation of fully functional mitochondria, both in cell culture and in vivo. Conversely, deletion of PGC-1α and β leads to mitochondrial defects in numerous tissues. To do this, the PGC-1s must coordinate the activation of 100s of genes, both on the nuclear and mitochondrial genomes. This occurs in part through co-activation of the nuclear respiratory factors (NRF-1 and 2), the orphan nuclear receptors ERRα and γ, and likely a number of other transcription factors.
We have recently shown that PGC-1α also regulates angiogenesis. PGC-1α regulates a broad angiogenic program, including the expression of VEGF and a number of other angiogenic factors, leading to a dramatic increase in vasculature density in PGC-1α transgenic animals. The induction of VEGF by PGC-1α requires the co-activation of ERRα on conserved binding sites found in the promoter and in a newly identified enhancer within the first intron of the VEGF gene. Hence, PGC-1α and ERRα, major regulators of mitochondrial function in response to exercise and other stimuli, also control a novel angiogenic pathway that delivers needed oxygen and substrates.
PGC-1 as a platform for discovery
We have leveraged the above observations and used the PGC-1s as discovery platforms in various contexts, with sometimes surprising findings:
PGC-1alpha is required for exercise-induced angiogenesis in skeletal muscle (PNAS ’09) and for mitochondrial biogenesis in response to calorie restriction (PNAS ’12). On the other hand, it is not required for exercise-induced mitochondrial biogenesis (PLOSone ’12).
PGC-1alpha is equally critical for angiogenesis in cardiac muscle, and aberrancies in this pathway lead to cardiomyopathy in mice. Interestingly this occurs only in the context of pregnancy, providing a novel model of Peripartum Cardiomyopathy (PPCM), a disease affecting approximately 1:2000 women worldwide. Studying this model has led to novel understanding of the disease, including the key notion that PPCM is fundamentally a vascular disease, triggered in part by anti-vascular hormonal insults from the placenta, and pathophysiologically related to preeclampsia, a common disease of late pregnancy (Nature ’12).
Probing the role of PGC-1alpha in tumors led us to melanoma and melanocytes, where we showed that PGC-1s and MITF, master regulator of melanocyte biology, mutually induce each other in a positive feedback loop. In melanocytes, the PGC-1s mediate the tanning response (Molecular Cell ’13), while in melanomas, PGC-1alpha drives critical metabolic responses that allow cells to evade chemotherapy (Cancer Cell ’13).
PGC-1alpha also plays an important role in angiogenesis in the eye (AJP ’13), and in endothelial cells themselves, where PGC-1alpha paradoxically inhibits angiogenesis via Notch activation (Cell Metabolism ’14).
The lab currently focuses on addressing a number of questions:
- What is the role of metabolism in vascular cells? Much is known of metabolism in cancer cells, and in parenchymal cells, but the role of metabolism in vascular cell biology has received little attention.
- What is the role of PGC-1 coactivators in regulating cardiac and skeletal muscle metabolism, and in regulating angiogenesis in various physiological and pathophysiological contexts?
- What molecular links exist between vascular metabolic health and systemic metabolic health, especially in the contexts of pregnancy and exercise (on the healthy side), and aging and diabetes (on the less healthy side)?
We take a multidisciplinary approach to these questions, ranging from molecular biology and high-throughput metabolomics (e.g. C13 flux analyses) and genomics to cell biology, mouse physiology, and human genetics. Our goal is to understand events that underlie physiological and pathological metabolic adaptations in heart, skeletal muscle, and the vasculature.