Molecular biology of primary pulmonary hypertension

Mehran Mandegar, Patricia A. Thistlethwaite, Jason X.J. Yuan

Research output: Contribution to journalReview articlepeer-review

10 Scopus citations


It is clear now that the etiology of PPH involves a heterogeneous constellation of multiple genetic, molecular, and humoral abnormalities. Studies have implicated derangements in multiple levels of genetic, molecular, cellular, hormonal, and humoral activity and function. For example, ion-channel synthetic, structural, and functional derangements (eg, decreased expression of functional KV channels) and multiple derangements in complex intracellular signaling pathways (eg, BMP and 5-HT signaling pathways) have been identified, all of which can contribute in different ways to the manifestation of this disease in different individuals. Although each abnormality seems important, none seems to be sufficient to cause the disease by itself. A complex web of interrelated events is often involved in the development of this process, which affects the pulmonary vasculature in a selective fashion. Some of the derangements, such as the BMPR2 gene mutations, occur in cells throughout the body, but disease manifests only in the pulmonary vascular bed. Therefore, inheritance of BMPR2 gene mutation by itself should not be sufficient for the development of PPH, and experts have proposed the multiple-hit theory in which some of the hits confer pulmonary specificity. For instance, inheritance of BMPR2 gene mutation followed by acquired mutations in KV channels can trigger the development of severe PPH. Taking all these factors into consideration, one can classify the abnormalities that are responsible for the development and maintenance of PPH into three broad categories: (1) cellular factors that create a proliferative, antiapoptotic, and vasoconstrictive physiologic milieu, (2) circulating factors that promote a proliferative, antiapoptotic, and vasoconstrictive physiologic milieu, and (3) genetic molecular signaling factors that promote gene transcription and the cellular synthetic cycle, thereby promoting a proliferative, antiapoptotic, and vasoconstrictive physiologic milieu. The final manifestation of all of these diverse abnormalities seems to be vascular remodeling that results from a disturbance in the fine balance between the proliferation and apoptosis of PASMCs and derangements in the vascular tone in which chronic and sustained vasoconstriction leads to medial hypertrophy of the small to medium-sized pulmonary arteries. Vascular remodeling consists of narrowing of the lumen of pulmonary arteries and arterioles, thereby increasing PVR, and ensuing pulmonary hypertension. As research aimed at discovering effective therapies for PPH continues, one should remember that the many diverse and often clinically occult abnormalities that have been implicated in the development of PPH seem to share one final pathway: vascular remodeling. Targeting vascular remodeling for therapeutic means would obviously be much more practical and effective than developing numerous therapeutic modalities to reverse each of the unique pathogenic derangements in any individual. The authors suggest that any effective future therapeutic modality should strive to prevent or reverse vascular remodeling by inhibiting proliferation and promoting apoptosis in PASMCs and possibly by attenuating the vascular tone and preventing vasoconstriction at a cellular level. A combined modality directed at these three fronts may provide synergistic effects and ultimately improve the prognosis for PPH.

Original languageEnglish (US)
Pages (from-to)417-429
Number of pages13
JournalCardiology clinics
Issue number3
StatePublished - Aug 2004
Externally publishedYes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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