Chronic Hypoxic Pulmonary Hypertension

Chronic hypoxic pulmonary hypertension is the consequence of both pulmonary vasoconstriction and remodeling. The importance of each component is still disputed. It is usually considered that proliferation (or decreased apoptosis) of cells in the intima, media and adventitia causes the vessel wall to intrude upon the lumen and pose a "fixed" resistance to flow through the lungs. Supporting this contention is the repeated observation that after

Figure 1. Effect of short-term (6 h [shaded bars], 12 h [striped bars], and 24 h [cross-hatched bars]) hypoxia on mRNA levels of Kv1.2, Kv1.5, and Kv2.1 -subunits in PASMCs. (A) PCR amplified products are displayed in agarose gel for Kv1.2, Kv1.5, Kv2.1 and P-actin transcripts. Lane 1 shows the molecular weight marker used to indicate the size of the PCR fragments. (B) Data were normalized to the amount of P-actin in PASMCs in normoxia (0 h) or after 6, 12, and 24 h moderate hypoxia. Values are means ± SEM (experiments were repeated 6 times independently). *P < 0.05, **P < 0.01 versus normoxic controls (0 h, open bar). (From Hong Z, Weir EK, Nelson DP, Olschewski A. Sub-acute hypoxia decreases Kv channel expression and function in pulmonary artery myocytes. Am J Respir Cell Mol Biol. 2004; 31: 337-343).

Figure 1. Effect of short-term (6 h [shaded bars], 12 h [striped bars], and 24 h [cross-hatched bars]) hypoxia on mRNA levels of Kv1.2, Kv1.5, and Kv2.1 -subunits in PASMCs. (A) PCR amplified products are displayed in agarose gel for Kv1.2, Kv1.5, Kv2.1 and P-actin transcripts. Lane 1 shows the molecular weight marker used to indicate the size of the PCR fragments. (B) Data were normalized to the amount of P-actin in PASMCs in normoxia (0 h) or after 6, 12, and 24 h moderate hypoxia. Values are means ± SEM (experiments were repeated 6 times independently). *P < 0.05, **P < 0.01 versus normoxic controls (0 h, open bar). (From Hong Z, Weir EK, Nelson DP, Olschewski A. Sub-acute hypoxia decreases Kv channel expression and function in pulmonary artery myocytes. Am J Respir Cell Mol Biol. 2004; 31: 337-343).

several weeks of hypoxia, return to normoxia or to hyperoxia does not rapidly restore pulmonary vascular resistance to pre-hypoxic levels. However, it has recently been reported that the compound Y-27632, which inhibits Rho kinase and calcium sensitization, will acutely reverse chronic hypoxic pulmonary hypertension. Thus, chronic hypoxia sets in play a signaling cascade causing vasoconstriction that persists when the hypoxic stimulus is removed. This signaling cascade can be rapidly interrupted by Y-27632, (but not immediately by oxygen), indicating that after a few weeks of hypoxia, although cell proliferation occurs, it is not the principal reason for pulmonary hypertension. It remains to be seen whether hypoxic pulmonary hypertension that has been present for several years can be so quickly reversed.

The effect of the Y-27632 compound indicates a role for calcium sensitization in the increased pulmonary vascular tone seen in chronic hypoxia. There is also evidence for the involvement of SOC and K+ channels. The expression of TRPC1 and 6 genes (which code for SOC channels) is increased in the PASMCs of both rats and mice exposed to hypoxia (10% O2) for three weeks [28]. The functional corollary of these observations is that capacitative (SOC) calcium entry is enhanced in PASMCs from the resistance pulmonary arteries of rats exposed to chronic hypoxia. The increased expression of TRPC 1 and 6 during hypoxia is absent in mice partially deficient for HIF-1a and, as a consequence, the resting cytosolic calcium is not elevated. The conclusion is that the stabilization of H1F-1a that occurs in hypoxia, leads to increased expression of TRPC1 and 6, which results in increased calcium entry [28].

Chronic hypoxia, over 12 hours in duration, results in decreased expression of oxygen-sensitive K+ channels (e.g. Kv 1.5 and 2.1) in the PASMCs and membrane depolarization [24] [16] [8] (Figure 1). The decreased expression of K+ channels in chronic hypoxia again involves H1F-1a [22]. In view of the decreased expression of K+ channels in chronic hypoxia and the role of K+ channels in acute HPV, it is not surprising that exposure to chronic hypoxia reduces acute HPV [11]. The finding that transfection of Kv 1.5 by aerosol can restore acute HPV indicates the importance of K+ channels in the pulmonary vascular response to hypoxia [19]. The K+ channels involved, include not only voltage-gated K+ channels but also two-pore acid-sensitive K+ channels (TASK channels) [15].

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