Cellular adaptation during chronic neonatal hypoxic pulmonary hypertension

K. R. Stenmark, A. A. Aldashev, E. C. Orton, A. G. Durmowicz, D. B. Badesch, W. C. Parks, R. P. Mecham, N. F. Voelkel, J. T. Reeves

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Newborn animals develop more severe hypoxic pulmonary hypertension than do adults, their vascular changes are greater, and both the hypertension and vascular changes occur more rapidly. We hypothesize that this differential developmentally controlled response may arise from either a difference in the type or quantity of endogenously secreted mediators in response to a given injury or a difference in the replicative and/or matrix-producing response of the vascular cells to physical or chemical stimuli. We investigated the effect of chronic hypoxia (14 days) on the proliferative and matrix-producing phenotype of the neonatal (14-day-old) pulmonary artery smooth muscle cell (SMC) and examined the heterogeneity and potential mechanisms responsible for this response. In situ hybridization studies demonstrated a remarkable change in the distribution of cells hybridizing with a tropoelastin cRNA probe after 14 days of hypoxia. Studies also demonstrated a population of SMC that did not hybridize with the elastin or collagen probes, indicating that the pulmonary artery contains SMC of multiple phenotypes and that the response to hypoxic and hemodynamic stress is not uniform for the various types. Bromodeoxyuridine labeling experiments indicated a large increase in DNA synthesis in hypertensive vessels, which, again, was not uniform either across or along the arterial wall. In vitro experiments with neonatal SMC suggested that hypoxia alone could not be responsible for the proliferative or matrix changes. These observations were supported by in vivo experiments in which coarctation of the left pulmonary artery, which markedly decreased pressure and flow to the left lung in hypoxic animals (14 days), resulted in significant decreases in collagen and elastin message levels in the left pulmonary artery distal to the coarctation compared with location-matched vessels from the right lung. Finally, we noted marked decreases in B-receptor density and adenyl cyclase activity in right atrial and pulmonary artery tissue from the chronically hypoxic animals. Decreases in the ability of the cell to produce adenosine 3',5'-cyclic monophosphate could significantly affect both the proliferative and matrix-producing potential of the SMC. We conclude that in vivo adaptation of the pulmonary artery SMC to chronic hypoxia includes changes in protein synthesis, cell proliferation, receptor expression, and enzyme activity. Further, there is a marked heterogeneity of these responses both across and along the arterial wall.

Original languageEnglish
Pages (from-to)97-104
Number of pages8
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume261
Issue number4 SUPPL.
DOIs
StatePublished - 1991
Externally publishedYes

Keywords

  • hypoxia
  • phenotype
  • signal transductions
  • smooth muscle cells

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