Molecular mechanisms controlling the coupled development of myocardium and coronary vasculature

Abstract

Cardiac failure affects 1.5% of the adult population and is predominantly caused by myocardial dysfunction secondary to coronary vascular insufficiency. Current therapeutic strategies improve prognosis only modestly, as the primary cause -- loss of normally functioning cardiac myocytes -- is not being corrected. Adult cardiac myocytes are unable to divide and regenerate to any significant extent following injury. New cardiac myocytes are, however, created during embryogenesis from progenitor cells and then by cell division from existing cardiac myocytes. This process is intimately linked to the development of coronary vasculature from progenitors originating in the endothelium, the proepicardial organ and neural crest. In this review, we systematically evaluate approx. 90 mouse mutations that impair heart muscle growth during development. These studies provide genetic evidence for interactions between myocytes, endothelium and cells derived from the proepicardial organ and the neural crest that co-ordinate myocardial and coronary vascular development. Conditional knockout and transgenic rescue experiments indicate that Vegfa, Bmpr1a (ALK3), Fgfr1/2, Mapk14 (p38), Hand1, Hand2, Gata4, Zfpm2 (FOG2), Srf and Txnrd2 in cardiac myocytes, Rxra and Wt1 in the proepicardial organ, EfnB2, Tek, Mapk7, Pten, Nf1 and Casp8 in the endothelium, and Bmpr1a and Pax3 in neural crest cells are key molecules controlling myocardial development. Coupling of myocardial and coronary development is mediated by BMP (bone morphogenetic protein), FGF (fibroblast growth factor) and VEGFA (vascular endothelial growth factor A) signalling, and also probably involves hypoxia. Pharmacological targeting of these molecules and pathways could, in principle, be used to recreate the embryonic state and achieve coupled myocardial and coronary vascular regeneration in failing hearts.

Abnormal Myocardial and Coronary Vasculature Development in Experimental Hypoxia

“…Deficient coronary development precludes compaction and is the basis of embryonic lethality in mice lacking coronary arteries (Kwee et al, 1995); reviewed in , or, when localized, could be a cause of recently recognized noncompacted cardiomyopathy (Varnava, 2001). Molecular mechanisms orchestrating coupled development between myocardium and coronary vasculature were recently summarized by Bhattacharya et al (2006), whereas current views on the genetic pathways controlling development of the coronary vasculature were reviewed by Olivey et al (2004). However, recent experimental study by Lavine et al (2008) have pointed out that regulation of cell proliferation in myocardium and coronary vasculature utilizes genetically distinct pathways.…”

Miocardiocitos conducentes ventriculares

“…[4][5][6] De la misma manera, Pax3 (paired box 3) determina en las células progenitoras la migración desde tres diferentes orígenes, los cuales corresponden al mesodermo cardiogénico, las células de la cresta neural y el órgano proepicardial, con el fin de proliferar y diferenciarse en un fenotipo contráctil de cardiomiocitos ( Figure 2). 7,8 El mesodermo cardiogénico se diferencia bajo la influencia de los factores de transcripción BMP-2 (bone morphogenic protein 2) y BMP-4 (bone morphogenic protein 4), producida por el endodermo faríngeo subyacente. Es responsable de la regulación de la expresión de FGF-8 (factor de crecimiento de los fibroblastos 8) un factor clave para la regulación de la síntesis de proteínas y, Cerberus, que inducen en las células del mesodermo esplácnico o visceral, la síntesis de Nkx2.5 para regular la expresión genética y la diferenciación celular de mioblastos cardiacos.…”

Myocardial Gene Expression Associated with Genetic Cardiac Hypertrophy in the Absence of Hypertension

“…The over-expression in old HHR of the guanine nucleotide binding protein gene (Gng5), Rab12 (a member of the Ras oncogene family) and mitogen activated protein kinase 1 (Mapk1) further suggests a role for the Ras/ MAPK signaling pathway in the etiology of cardiac enlargement in the HHR. Evidence that MAPK1 (27)(28)(29), MAPK14 (30,31) and MAP2K4 (32) are involved in normal and abnormal tissue growth further strengthens the possibility that these are key enzymes in the cardiotrophic process in the HHR. However, the cause and effect relationship between the activity of these enzymes and the elevated cardiac size of the HHR remains to be determined.…”