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/