Mobilization of SR Ca2 Stores by Hypoxia in Pulmonary Artery Smooth Muscle

Our findings are consistent with the view that hypoxia mobilizes smooth muscle SR Ca2+ stores by at least two discrete mechanisms, and thereby initiates

HPV. The initial transient constriction of isolated pulmonary arteries by hypoxia (component 1), appears to be mediated by metabolic inhibition of an SR Ca2+ ATPase (SERCA) subtype that serves the peripheral SR proximal to the plasma membrane, or by an as yet unidentified mechanism. In marked contrast, we have provided strong evidence to support our assertion that maintained smooth muscle constriction by hypoxia (component 2) is mediated by sustained Ca2+ release from a central SR compartment. And that this results from, at least in part, activation of ryanodine receptors (RyRs) by cyclic adenosine diphosphate-ribose (cADPR), a Ca2+ mobilizing messenger derived from P-NAD+ (55).

Figure 1. Three components of HPV, the distribution of the enzyme activities for cADPR production and metabolism in pulmonary versus systemic arteries, and increased cADPR accumulation in pulmonary arteries by hypoxia. A: Three components of constriction by hypoxia of isolated pulmonary arteries; 1, cADPR-independent SR Ca2+ release in the smooth muscle; 2, cADPR-dependent SR Ca2+ release in the smooth muscle; 3, release of an endothelium-derived vasoconstrictor, B and C: Synthesis of cADPR from p-NAD+ (B) and metabolism of cADPR (C) in smooth muscle homogenates from a series of pulmonary (PA) and mesenteric (MA) arteries. D: Relative cADPR levels in 2nd and 3rd order branches of the pulmonary artery, respectively, during normoxia (Nor) and hypoxia (Hyp).

Figure 1. Three components of HPV, the distribution of the enzyme activities for cADPR production and metabolism in pulmonary versus systemic arteries, and increased cADPR accumulation in pulmonary arteries by hypoxia. A: Three components of constriction by hypoxia of isolated pulmonary arteries; 1, cADPR-independent SR Ca2+ release in the smooth muscle; 2, cADPR-dependent SR Ca2+ release in the smooth muscle; 3, release of an endothelium-derived vasoconstrictor, B and C: Synthesis of cADPR from p-NAD+ (B) and metabolism of cADPR (C) in smooth muscle homogenates from a series of pulmonary (PA) and mesenteric (MA) arteries. D: Relative cADPR levels in 2nd and 3rd order branches of the pulmonary artery, respectively, during normoxia (Nor) and hypoxia (Hyp).

Our findings therefore suggest that cADPR accumulation by hypoxia represents one of a number of diverging processes that may or may not be of primary importance to the regulation of a given type of02-sensing cell. This is clear from the finding that cADPR does not appear to play a primary role in mediating the initial transient constriction of pulmonary artery smooth muscle by hypoxia, or in mediating vasoconstrictor release by hypoxia from the pulmonary artery endothelium (see Chapter 6 and 12). Thus, regulation by hypoxia of cADPR accumulation likely represents a point of bifurcation in the proposed 02-sensitive signaling cascade within pulmonary artery smooth muscle. We will proceed, therefore, with the premise that a common metabolic signaling pathway exists in all cells, and that this may promote, among other events, cADPR accumulation by hypoxia in a manner dependent on the "metabolic setting" of a given cell. If this is the case, identification of the precise mechanism by which hypoxia regulates cADPR synthesis will lead us to the identification of the "primary metabolic sensor" and "primary effector", respectively, in 02-sensing cells.

Was this article helpful?

0 0
Reducing Blood Pressure Naturally

Reducing Blood Pressure Naturally

Do You Suffer From High Blood Pressure? Do You Feel Like This Silent Killer Might Be Stalking You? Have you been diagnosed or pre-hypertension and hypertension? Then JOIN THE CROWD Nearly 1 in 3 adults in the United States suffer from High Blood Pressure and only 1 in 3 adults are actually aware that they have it.

Get My Free Ebook


Post a comment