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Heart 3:Organogenesis, CHD, prenatal circulation
• Heart development
• Development
of vasculature
• Pathogenesis of CHD
• Prenatal circulation
and its remodeling
after birth
David SedmeraCharles University
First Faculty of Medicine
Institute of Anatomy
Molecular control of cardiogenesis
Formation of the heart tube
Morphogenesis of the heart
Cardiac tube & its looping
Septation of atria and ventricles
Morfogenetic mechanisms
• Proliferation
• Migration
• Diferentiation
• Cell death (programmed)
Outflow tract septation
Role of neural crest in outflow tract
septation
NB coronary
vessels also
have
extracardiac
origin
Analysis of neural crest cell migration using
chick - quail chimera
aortico-pulmonary septum!
Electrocardiogram (ECG)
Embryonic conduction system
LARA
RV
LV
Visualization of embryonic CCS
Isochronal activation maps
Conserved among species (homeioterms)
Development of coronary vessels
EPDCs
Congenital heart disease
• Cardiac tube - cardia bifida (lethal)
• Impaired looping - dextrocardia
• Deficient septation - ASD, VSD
• Outflow tract defects - PTA, DORV, TGA
• TOF (cyanotic, common, complex)
• PDA (relatively common, extracardiac)
• Causes: genetics (Down’s, Nkx2.5 mutations), environment / drugs (ethanol, Etretinate, …)
Factors influencing development
• Genetic (dominant and recessive alleles,
interactions, variants …)
• Physical (mechanical, ionizing radiation,
temperature, hypoxia)
• Chemical (teratogens, ionic disequilibrium,
vitamins, hormonal dysbalance, hyperglycemia…)
• Biological (bacteria, viruses, parasites)
Chick embryonic model
Hypoplastic left heart syndrome
(HLHS)
Vasculogenesis vs. Angiogenesis
Origin of endothelial cells
1. Mesenchyme precursor cell
(hemangioblast, prumary angioblast, determined by FGF)
Lokalization:
Extraembryonic – yolk sac
intraembryonic mesoderm - somites, splanchnopleura
alantois ?
Blood islands
Vessels de novo
vaskulogenesis
C-myb
Vasculogenesis
Aortico-gonadal region
Formation of
blood and
endothelial cells
in ventral aortic
wall
HC - CD 45 +
EC - VEGFR2+
Hematopoiesis during prenatal development
Angiogenesis
Sprouting
Tip formation
Migration
Lumen formation
Connection
Establishment of flow
Pericytes
Vessel maturation
Mechanisms of angiogenesis
1) intususception growth
2) intercalar growth
3) fusion
5) remodling
6) pruning
Organotypic endotelial diferentiation
interaction with parenchymal cells
Pores and fenestrations
Specific receptors and enzymes
Pro-Angiogenic growth factors
VEGF (vascular endothelial gowth factor)A, - B, - C, - D, - E
PlGF (placental growth f.),
PDGF (platelet derived growth f.)
GF receptors:(RTK activity)
VEGFR-1 (Flt1)
VEGFR-2 (Flk1, KDR, Quek1)
VEGFR-3 (Flt-4, Quek2)
VEGF A - VEGFR 2
different isoforms of VEGF A
(alternative splicing)
increases permeability
expression stimulated by hypoxia
VEGF B - VEGFR 1heart and skeletal muscle
not dependent on tissue hypoxia
VEGF C - VEGFR 3proliferation of lymphatic
endothelium
More angiogenic growth factors:Angiopoetin -1, -2 /
receptor Tie 1, Tie 2
structural vessel integrity
Remodling, cell adhesion
Ang 1 – emrbyonic
Ang 2 – adulthood in areas
of active remodeling
Defect of Tie2 receptor
Determination of arterio-venous identity:
Ephrin B2 / receptor EphB4
Vessels and nerves growth together (same signaling
molecules)
Lymfangiogenesis
GF and receptor:
VEGF-C VEGFR-3
Transcription factor Prox1
Syk / SLP 76 ??
Aortic arch derivatives
I a. maxillaris
II a. hyoidea, a. stapedia
III a. carotis communis,
první úsek a. carotis
interna
IV Aortic arch from a.
carotis communis to
a. subclavia sin.
a. subclavia
dx.(proximal segment)
VI a. pulmonalis sin.,
ductus arteriosus
a. pulmonalis dx.
Right-sided aortich arch
(!standard in birds)
Coarctation of the aorta (pre and post ductal
type, collateral circulation
Anomalous origin –
retreoesophageal right
subclavian artery (a. lusoria)
Double aortic arch – can
cause breathing or swallowing
difficulties
in utero
Fetal and
postnatal
circulation
post partum
Fetal and postnatal
circulation
Remodeling after
birth
References
• Milan Klima (heart picture)
• Sadler: Human Embryology
• Ondrej Nanka (angiogenesis)
• Original research papers
• Venous system development:https://www.phlebolymphology.org/venous-embryology-the-key-to-understanding-
anomalous-venous-conditions/