Metabolism and Energetics of Vascular Smooth Muscle

Hardin, Christopher D.; Allen, Tara; Rutgeerts, Paul

doi:10.1016/b978-012656975-9/50035-3

Cited by 9 publications

(9 citation statements)

References 113 publications

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“…Thus under anoxic/hypoxic conditions, systemic vessels can maintain low [Ca 2+ ] i and some level of reversible contractile function. These observations can in part be explained by a robust glycolytic capacity [123]. which preferentially supports membrane ion pumps in VSM [124].…”

Section: Interactionsmentioning

confidence: 94%

Ca2+ Clearance and contractility in vascular smooth muscle: Evidence from gene-altered murine models

Oloizia

Rutgeerts

2008

Journal of Molecular and Cellular Cardiology

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The central importance of calcium clearance proteins, and their regulators, in the modulation of myocardial contractility and intracellular Ca 2+ concentration ([Ca 2+ ] i ) has long been established. Key players identified include the Na + -Ca 2+ exchanger, the Na + -K + ATPase, the sarco(endo)plasmic reticulum Ca 2+ -ATPase and associated phospholamban. Gene-targeted and transgenic murine models have been critical in the elucidation of their function. The study of these proteins in the regulation of contractile parameters in vascular smooth muscle, on the other hand, is less well studied. More recently, gene-targeted and transgenic models have expanded our knowledge of Ca 2+ clearance proteins and their role in both tonic and phasic smooth muscle contractility. In this review, we will briefly treat the mechanisms which underlie Ca 2+ clearance in smooth muscle. These will be addressed in light of studies using gene-modified mouse models, the results of which will be compared and contrasted with those in the cardiomyocyte. The recently identified human mutations in phospholamban, which lead to dilated cardiomyopathy, are also present in vascular and other smooth muscle. Given the importance of these Ca 2+ clearance systems to modulation of smooth muscle, it is likely that mutations will also lead to smooth muscle pathology. Ca 2+ CLEARANCE AND REGULATION OF [Ca 2+ ] iCa 2+ homeostasis is central to the regulation of smooth muscle function. It is well established that [Ca 2+ ] i plays an essential role in the activation of myosin light chain kinase, which phosphorylates myosin, thereby activating the actin-myosin interaction (for review see [1]). It has also be estimated that Ca 2+ influx under basal conditions is 16 μmole/liter per minute, more than 2 orders of magnitude greater than the resting [Ca 2+ ] i . Thus Ca 2+ clearance from the cytosol is critical to the maintenance of a quiescent baseline and is a major factor in modulation of Ca 2+ homeostasis and thus contractile force. The plasma membrane Ca 2+ ATPase (PMCA), sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA), Na + -Ca 2+ -exchanger (NCX) and mitochondria all function to some extent in this process (for reviews see [2,3]). Figure 1 shows a schematic illustration of these Ca 2+ clearance pathways. Also of importance to smooth muscle Ca 2+ clearance are phospholamban (PLN), an endogenous inhibitor of SERCA, and the Na + -K + ATPase (NKA), which couples to NCX, and facilitates the extrusion of Ca 2+ via the forward mode of the exchanger. NCX is generally considered to be a high-capacity exchanger, i.e., low affinity for Ca 2+ (K d ≈1 μM), but high turnover [4][5][6][7]. SERCA and PMCA, on the other hand, have a higher affinity for Ca 2+ (K d ≈0.1-0.3 μM) [6,[8][9][10][11], but lower turnover than NCX. For smooth muscle, the relative contribution of each to Ca 2+ clearance is dependent on conditions and smooth muscle type, but in general, NCX accounts for about 60%, while PMCA and Publisher's Disclaimer: This is a PDF file of an unedited manu...

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Section: Interactionsmentioning

confidence: 94%

Ca2+ Clearance and contractility in vascular smooth muscle: Evidence from gene-altered murine models

Oloizia

Rutgeerts

2008

Journal of Molecular and Cellular Cardiology

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“…Using 13 C NMR to examine the products of metabolism from glycolysis and gluconeogenesis (which share 8 common enzymes), we have determined that glycolysis and gluconeogenesis occur in separate compartments within the VSM cell and that their respective intermediates do not mix freely within the cytoplasm (19,20,22,(33)(34)(35). Here we used 13 C NMR to demonstrate that compartmentation of glycolysis from gluconeogenesis also exists in cultured A7r5 VSM cells (Fig.…”

Section: Metabolic Compartmentation In Vsm Cells and The Role Of The mentioning

confidence: 99%

“…Previous work by our laboratory has shown that glycolysis and gluconeogenesis occur in separate compartments within the cell and that their intermediates do not mix freely in the cytoplasm of vascular smooth muscle (VSM) cells (19,20,22,33,34). We have also found that an intact plasma membrane is essential for compartmentation of glycolysis from gluconeogenesis to exist, suggesting that glycolysis and gluconeogenesis may be associated with distinct plasma membrane microdomains (34,35), and that disruption of the specific caveolae plasma membrane microdomains by treatment with cyclodextrin disrupts metabolic flux and compartmentation in VSM cells (35).…”

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confidence: 99%

Metabolic organization in vascular smooth muscle: distribution and localization of caveolin-1 and phosphofructokinase

Vallejo

Hardin

2004

American Journal of Physiology-Cell Physiology

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We have shown that a compartmentation of glycolysis and gluconeogenesis exists in vascular smooth muscle (VSM) and that an intact plasma membrane is essential for compartmentation. Previously, we observed that disruption of the caveolae inhibited glycolysis but stimulated gluconeogenesis, suggesting a link between caveolae and glycolysis. We hypothesized that glycolytic enzymes specifically localize to caveolae. We used confocal microscopy to determine the localization of caveolin-1 (CAV-1) and phosphofructokinase (PFK) in freshly isolated VSM cells and cultured A7r5 cells. Freshly isolated cells exhibited a peripheral (membrane) localization of CAV-1 with 85.3% overlap with PFK. However, only 59.9% of PFK was localized with CAV-1, indicating a wider distribution of PFK than CAV-1. A7r5 cells exhibited compartmentation of glycolysis and gluconeogenesis and displayed two apparent phenotypes distinguishable by shape (spindle and ovoid shaped). In both phenotypes, CAV-1 fluorescence overlapped with PFK fluorescence (83.1 and 81.5%, respectively). However, the overlap of PFK with CAV-1 was lower in the ovoid-shaped (35.9%) than the spindle-shaped cells (53.7%). There was also a progressive shift in pattern of colocalization from primarily the membrane in spindle-shaped cells (both freshly isolated and cultured cells) to primarily the cytoplasm in ovoid-shaped cells. Overall, cellular colocalization of PFK with CAV-1 was significant in all cell types (0.68 ≥ R2 ≤ 0.77). Coimmunoprecipitation of PFK with CAV-1 further validated the possible interaction between the proteins. We conclude that a similar distribution of one pool of PFK with CAV-1 contributes to the compartmentation of glycolysis from gluconeogenesis.

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“…The more poorly ventilated (oxygenated) a given pulmonary smooth muscle cell is, the more important is its constrictive response. Fortunately, vascular smooth muscle cells are highly glycolytic and normally derive 20-30 % of cell ATP production from glucose conversion to lactate which does not require oxygen (Hardin et al 2001). By being highly glycolytic, smooth muscle can maintain force under hypoxic conditions as long as glucose is present, as would occur with poor ventilation and adequate perfusion.…”

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confidence: 99%

“…Therefore, glycolysis seemed to be necessary for the calcium sensitization via the activity of Rho kinase. This intriguing proposal that glycolysis may be coupled to a cell signalling kinase is an important addition to the growing body of evidence that glycolysis is specifically coupled to a variety of ATP-requiring processes within the smooth muscle cell (Hardin et al 2001).…”

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Making sense of oxygen sensing

Hardin

2001

The Journal of Physiology

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Matching blood flow to lung ventilation is a tricky feat in which the tone of the pulmonary resistance vessels must be exquisitely matched to nearby oxygen tension. Without such matching of ventilation to perfusion, arterial blood oxygen tension cannot be maintained near that of the ambient atmosphere. Hypoxia-induced pulmonary vasoconstriction (HPV) shunts blood flow from poorly ventilated regions of the lung to better ventilated regions. How does the pulmonary vasculature 'sense' decreased oxygen tension and how is increased contractile force coupled to these sensing mechanisms?The response of the pulmonary circulation to hypoxia is opposite to that of the systemic circulation. In the systemic circulation regions of hypoxia may be underperfused relative to energy demand and hence vasodilate to increase perfusion to match oxygen supply to energy demand. The mechanisms for hypoxia-induced vasorelaxation are intuitively easier to understand and a variety of mechanisms have been proposed over the years including local adenosine and lactic acid production, endothelial nitric oxide production, and simply reduced energy charge within the hypoxic smooth muscle resulting from hypoxia and causing decreased contractile tone.In the pulmonary vasculature during hypoxia, HPV increases energy demand of the smooth muscle in the face of decreased oxygen availability for oxidative energy production. The smooth muscle cell faces a conundrum of increasing energy expenditure in the face of limits to oxidative energy production. The more poorly ventilated (oxygenated) a given pulmonary smooth muscle cell is, the more important is its constrictive response. Fortunately, vascular smooth muscle cells are highly glycolytic and normally derive 20-30 % of cell ATP production from glucose conversion to lactate which does not require oxygen (Hardin et al. 2001). By being highly glycolytic, smooth muscle can maintain force under hypoxic conditions as long as glucose is present, as would occur with poor ventilation and adequate perfusion. However, two aspects of HPV have remained mysterious and controversial over the years: (1) the nature of the oxygen sensor and the downstream signals to initially raise intracellular calcium to increase smooth muscle force generation and (2) the mechanisms by which HPV is maintained for prolonged periods in the face of attenuated intracellular free calcium concentration (calcium sensitization of contraction).

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Metabolism and Energetics of Vascular Smooth Muscle

Cited by 9 publications

References 113 publications

Ca2+ Clearance and contractility in vascular smooth muscle: Evidence from gene-altered murine models

Ca2+ Clearance and contractility in vascular smooth muscle: Evidence from gene-altered murine models

Metabolic organization in vascular smooth muscle: distribution and localization of caveolin-1 and phosphofructokinase

Making sense of oxygen sensing

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