Pathobiology of Severe Pulmonary Hypertension

  • Geraci, Mark, (PI)
  • Franklin, Wilbur (PI)
  • Abman, Steven Herbert (PI)
  • Tuder, Rubin (PI)
  • Voelkel, Norbert (PI)

Project: Research project


DESCRIPTION (provided by applicant):
This PPG application has evolved from three presently active R01 grants, which
this application intends to replace. Severe chronic pulmonary hypertension
(PH) - in spite of intravenous prostacyclin (PGI2) treatment - remains an
important and challenging clinical problem. Our four projects have been
designed to investigate specific aspects of human PH including primary and
neonatal pulmonary hypertension. We start with the concept that pulmonary
arteries differ from systemic vessels in that their response to "stress" or
"injury" is different. We further postulate that the adult lung circulation
remodels with endothelial cell proliferation (Project 1), whereas the neonatal
lung circulation remodels without endothelial cell proliferation (Project 2).
Vascular endothelial growth factor (VEGF) and its receptor, KDR. are
critically involved in the formation of plexiform lesions in adult PH whereas
reduced VEGF/KDR signaling in the fetus leads to a vasculogenesis failure
characterized by a muscularized, pruned vascular tree. Project 3 develops
a prospectively designed new rodent model of endothelial cell-proliferative,
severe PH that has been built on inhibition of the VEGF receptor KDP, and
proposes that endothelial cell death selects for the emergence of resistant,
proliferative endothelial cells at sites of high shear stress. We anticipate
that this rat model will permit the systematic investigation of the interplay
between altered vasoreactivity (vasoconstriction) and development of
obliterative pulmonary vascular arteriopathy. The information gathered from
this model will include lung tissue transcript information gathered using the
microarray GeneChip technology and will be compared with the gene expression
data obtained from human PPH and 2nd PH lungs (Project 1). The fact that
endothelial cell proliferation in PPH is monoclonal encourages the search for
gene mutations. One candidate mutated gene is the TGF-B-RII gene coding for
the TGF-B-II receptor, which is involved in cell growth/death control. Lastly,
a severe loss of prostacyclin receptor (PGII-R) expression in the resistance
vessels of PPH lungs provides rationale and focus for the investigation of the
role of PGI2 and its receptor in pulmonary vascular remodeling (Project 4).
Vascular smooth muscle cells from genetically engineered mice (Lung-specific
PGI2-synthase gene overexpression and PGI2-receptor knock-out) will be
examined for PGI2-R-dependent and independent growth. We believe that this
highly integrated program addresses central issues of the pathobiology of
severe human pulmonary hypertension.
Effective start/end date9/17/017/31/07


  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health


Epoprostenol Receptors
Smooth Muscle Myocytes
Vascular Smooth Muscle
Pulmonary Hypertension
Blood Vessels
Peroxisome Proliferator-Activated Receptors
Genetically Modified Animals
Microarray Analysis
Cytoplasmic and Nuclear Receptors
prostacyclin synthetase
Intravenous Infusions
Knockout Mice
Vascular Remodeling
Signal Transduction
Blood Platelets
Animal Models


  • Medicine(all)