Heart Dev 2 Flashcards
Mechanical Forces in the Cardiovascular System
Pressure forces: Created by heart contractions and blood resistance in vessels.
Stretch/contractile forces: Due to heart muscle (cardiomyocytes) contractions, stretching and squeezing blood through the system.
Shear stress: The frictional force of blood flow against the vessel walls, affecting endothelial cells.
Hemodynamics (Blood Flow Dynamics)
Laminar flow: Smooth, orderly blood flow in parallel layers (normal in most arteries).
Turbulent flow: Chaotic, swirling blood flow, which can happen in areas of high velocity, narrowing, or plaque buildup (e.g., in the aorta).
Wall Shear Stress (WSS) & Shear Rate
Wall Shear Stress (WSS): The force that blood exerts on vessel walls.
- Velocity is highest in the center of the vessel.
- Shear rate (friction) is highest at the wall.
Higher blood flow or vessel narrowing = increased WSS.
Septation of the Atria and Ventricles
Goal: To form separate right and left heart chambers.
Process:
- Septum primum grows down from the top, partially dividing the atria.
- A hole (foramen primum) is present but closes as the septum fuses with the endocardial cushions.
- New holes (foramen secundum) form in the septum primum to maintain blood flow.
- Septum secundum forms next to it, covering the foramen secundum but leaving the foramen ovale open.
- After birth, the foramen ovale closes due to pressure changes.
Clinical Relevance: If the foramen ovale doesn’t close, it results in a patent foramen ovale (PFO), allowing abnormal blood mixing.
Neural Crest Cells in the Heart
Where do they come from? → Neural crest cells originate from the ectoderm and migrate into the developing heart.
What do they do? → They help form:
Endocardial cushions (which later form heart valves).
Outflow tract septation (separates the aorta and pulmonary artery).
Why is this important? → If neural crest migration is impaired, it can cause congenital heart defects like:
Persistent truncus arteriosus (failure to separate the aorta and pulmonary artery).
Tetralogy of Fallot (mixing of oxygenated and deoxygenated blood).
Aortic arch abnormalities.
Endocardial-Derived Mesenchyme & Dorsal Mesenchymal Cap
Endocardial-derived mesenchyme forms a structure called the dorsal mesenchymal cap, which helps create the septum primum.
The septum primum is a thin tissue that begins forming a wall between the right and left atria.
Cells migrate from the 2nd heart field into this cap, helping develop the heart chambers.
Septum Primum
first wall that starts forming between the right and left atria during fetal heart development.
=> grows downward from the roof of the atrium, moving toward the endocardial cushions in the middle of the heart.
It has a temporary hole (foramen primum) that allows blood to pass between the atria in early development.
[ the septum secundum (a second, thicker wall) develops next to the septum primum, with the foramen ovale]
What are the 1st and 2nd Heart Fields?
The heart fields refer to different populations of cells that contribute to heart development.
1st Heart Field (FHF)
Forms early in heart development.
Develops into the left ventricle and parts of the atria.
2nd Heart Field (SHF)
Contributes to more complex heart structures, including:
Right ventricle
Outflow tract (aorta & pulmonary artery)
Parts of the atria
Cells from the SHF migrate and are regulated by signals like SHH (Sonic Hedgehog) to guide proper formation.
What is SHH (Sonic Hedgehog) Signaling?
SHH (Sonic Hedgehog) is a signaling molecule that regulates cell migration and development.
It helps direct the migration of neural crest cells to ensure proper formation of the heart’s septation and valves.
Embryonic Blood Flow and Shunting
Before birth: Blood bypasses the lungs via the foramen ovale (right atrium → left atrium).
[ Foramen ovale (holes) = shunt (blood flow in
a specific place & direction)
* Enables oxygenated blood (coming from umbilical
vein) to pass from the right to the left atrium
* Oxygenated blood goes to the rest of the growing
embryo]
Why? Lungs are not yet functional,
==> Lungs don’t have air, vessels in the lungs are
constricted. Therefore, resistance to blood flow is
high and pressure in RA is high.
* Blood is pushed into the LA via the Foramen ovale
* ‘Holes’ fuse/filled in after birth (~3 months after):
septum secundum is thicker and septum primum
is pushed up against it when pressure is LA
so blood is shunted to systemic circulation.
After birth: The foramen ovale closes, separating pulmonary and systemic circulation.
Endocardial Cushion Cells & EMT (Epithelial-to-Mesenchymal Transition)
What’s happening here?
Epicardial-derived cells migrate and contribute to the valve formation.
Endocardial cushion cells help form the valve leaflets, chordae tendineae, and papillary muscles.
EMT (Epithelial-to-Mesenchymal Transition) occurs:
-> Cells change from an epithelial (sheet-like) state into mesenchymal (mobile) cells that can migrate and form heart structures.
Blood flow from the atria applies pressure and shear stress, stimulating this growth.
Why is this important?
These cushions later become the mitral (bicuspid) and tricuspid valves.
Defects here can cause congenital valve disorders.
Ventricular Septation (Muscular Ventricular Septum)
What’s happening here?
The muscular ventricular septum grows upward from the bottom of the ventricles.
It partially separates the left and right ventricles.
Why is this important?
If this septum fails to fully develop, it can lead to a ventricular septal defect (VSD), where oxygen-rich and oxygen-poor blood mix.
Atrioventricular (AV) Septum & Outflow Tract Formation
What’s happening here?
The atrioventricular (AV) septum forms, separating the atria from the ventricles.
The bulbar ridge grows downward, contributing to the outflow tract (aorta & pulmonary artery).
Why is this important?
The proper formation of the AV septum ensures correct alignment of the valves and ventricles.
Defects here can lead to AV septal defects, which can cause abnormal blood flow between the heart chambers.
Trabeculation
Trabeculae carneae are muscle ridges that form in the ventricles.
These increase heart efficiency by improving contraction and blood flow.
Controlled by Notch-1 and VEGF signaling.
How Does the AV Septum Relate to the Outflow Tract?
The bulbar ridge is part of the outflow tract, which gives rise to the aorta and pulmonary artery.
The AV septum helps anchor the developing outflow tract to the lower part of the heart.
As the bulbar ridge grows downward, it connects with the AV septum, ensuring the aorta and pulmonary artery align correctly with the ventricles.
bulbar ridge
The bulbar ridge is a structure that forms inside the outflow tract of the heart.
It is made of neural crest cells and endocardial cushion cells.
It plays a role in separating the aorta and pulmonary artery.
Valve Formation
Atrioventricular (AV) valves (mitral & tricuspid) form from endocardial cushions.
Semilunar valves (aortic & pulmonary) form from the outflow tract cushions.
Truncus Arteriosus
What is it?
The early structure that forms the main arteries leaving the heart.
What does it develop into?
Aorta (from left ventricle).
Pulmonary artery (from right ventricle).
The aorticopulmonary septum forms inside it, separating these two vessels.
Cell origin?
Neural crest cells (form the spiral septum inside).
Endocardial cushion cells (help with vessel separation).
Endocardial cushions
1️⃣ Atrioventricular (AV) Cushions → Form the AV valves (mitral & tricuspid) and part of the septa.
Made from: Endocardial-derived mesenchyme (NOT neural crest cells).
2️⃣ Outflow Tract (OFT) Cushions → Form the aortic & pulmonary valves and part of the outflow tract septum.
Made from: Neural crest cells (NCCs) + Endocardial cells.
Truncus Arteriosus
What is it?
The early structure that forms the main arteries leaving the heart.
What does it develop into?
Aorta (from left ventricle).
Pulmonary artery (from right ventricle).
The aorticopulmonary septum forms inside it, separating these two vessels.
Cell origin?
Neural crest cells (form the spiral septum inside).
Endocardial cushion cells (help with vessel separation).
Septation: Outflow tracks
Outflow track regulation
* Neural crest cells (NCC) and
endocardial cushion cell undergo
EMT [OFT cushion]
FGF8 signals Tbx1 for outflow tract development
=> Fibroblast Growth Factor 8) is a signaling molecule needed for proper OFT formation.
=> activates Tbx1, a transcription factor that controls the growth and division of cells in the outflow tract.
2️⃣ Second heart field (SHF) cells express Isl-1 and Hes-1 and migrate in
Second Heart Field (SHF) contributes to the right ventricle and outflow tract.
SHF cells express Isl-1 and Hes-1, which are genes important for cell migration and proliferation.
These cells migrate into the developing outflow tract to form part of the great arteries.
3️⃣ Apoptosis of NCC (Neural Crest Cells) and replacement by myocardial cells = myocardialization
Initially, Neural Crest Cells (NCCs) contribute to forming the outflow tract.
Later, some NCCs undergo apoptosis (programmed cell death).
They are replaced by myocardial (heart muscle) cells, which help the outflow tract become part of the heart muscle.
This process is called myocardialization.
4️⃣ Mediated by TGF-β, which signals migration and differentiation of cardiomyocytes
TGF-β (Transforming Growth Factor Beta) helps regulate cell behavior.
It signals cardiomyocytes to migrate and differentiate (develop into specialized heart cells).
This ensures the outflow tract properly integrates into the rest of the heart.
What is a Heart Field?
A heart field is NOT a physical tissue but rather a region of cells in the embryo that will migrate, proliferate, and form different parts of the heart.
Think of heart fields like blueprints—they tell cells where to go and what to become as the heart develops.
Two Main Heart Fields
1️⃣ First Heart Field (FHF) → Forms the Left Ventricle
Earliest heart-forming region.
Gives rise to the primary heart tube, which later becomes the left ventricle and part of the atria.
Cells from here stay in place and differentiate into heart muscle.
2️⃣ Second Heart Field (SHF) → Forms the Right Ventricle & Outflow Tract
Cells from the SHF migrate to extend the heart tube.
They form the right ventricle, outflow tract (OFT), and parts of the atria.
SHF is regulated by Isl-1 and Hes-1, which guide cell movement and proliferation.
How Do Heart Fields Work?
🔹 Think of the heart fields as “command centers” that send out cells to build the heart in different stages.
🔹 Cells don’t just stay in one place—they move (migrate) to the right location and differentiate into heart structures.
🔹 SHF is crucial for the outflow tract—without it, the aorta and pulmonary artery wouldn’t form properly.
Embryonic Circulation
The placenta oxygenates the blood (before birth in a fetus).
The heart just moves the blood to the right places at the right times.
Before Birth (Fetal Circulation):
Oxygenation happens in the placenta, NOT in the lungs.
The heart just directs the oxygenated blood to the body using shunts (Foramen Ovale & Ductus Arteriosus) to bypass the lungs.
1️⃣ Oxygenated blood from the placenta enters via the umbilical vein.
It bypasses the liver via the ductus venosus and goes to the inferior vena cava (IVC) → Right Atrium.
2️⃣ Two Key Lung Bypasses:
Foramen Ovale: A hole between the atria shunts oxygenated blood from the RA to the LA, skipping the lungs.
Ductus Arteriosus: Any blood that does go into the right ventricle and pulmonary artery is shunted into the aorta (bypassing the lungs).
3️⃣ Oxygenated blood in the aorta goes to the body & back to the placenta via the umbilical arteries.
Closure of Ductus arteriosus at birth
3 mechanisms to regulate DA closure
- Increase in Bradykinin after birth
Bradykinin is a chemical released from the lungs when they inflate with air for the first time.
It causes the DA to contract and close.
This only happens when oxygen levels are high (>50mmHg in the aorta).
Basically, as the baby starts breathing, the lungs release bradykinin → DA constricts → closes off. - Increase in oxygen
Oxygen plays a direct role in DA closure.
Oxygen blocks potassium channels in the smooth muscle of the DA, which lets calcium enter the cells.
Calcium = muscle contraction, so the DA closes when oxygen levels rise.
Since the baby starts breathing at birth, oxygen levels increase, and the DA closes naturally. - Reduction in Prostaglandins after birth
Prostaglandins (PGE2 and PGI2) keep the DA open during fetal life.
These prostaglandins are produced by the placenta, but when the umbilical cord is cut, their levels drop.
Low prostaglandins → DA muscles contract → DA closes.
Mechanical forces shape heart development
Mechanoreceptors on cell surfaces detect pressure or blood flow changes and trigger cellular responses, like gene expression changes, cytoskeleton adjustments, or cell proliferation.
2️⃣ Pressure Forces in Heart Development
==> pressure is a driving force for heart development because blood flow and mechanical forces shape the heart’s growth.
Early Pressure: As the heart tube forms, fluid movement inside creates pressure that stimulates tissue growth and remodeling.
==> Before the heart is fully formed, the primitive heart tube grows because of increasing internal pressure.
Blood Flow Pressure: Increased blood flow and circulation drive the formation of valves, chambers, and muscle thickening.
==> Higher pressure = stronger tissue:
Endocardial cushions elongate (important for septation).
ECM (extracellular matrix) expression increases, making valve leaflets stiffer.
Ventricular Pressure: Pressure inside the ventricles triggers myocyte proliferation, making the heart stronger.
==> Increased pressure in ventricles = more myocyte (heart muscle) proliferation
This helps the ventricles grow and mature properly.
3️⃣ Shear Stress in Heart Development
💡 Shear stress = The force of blood flowing along the vessel walls
TGF-β (Transforming Growth Factor Beta) is activated by shear stress
This helps in atrioventricular (AV) septation
Also promotes myocardialization (conversion of non-muscular cells into cardiac muscle).
VEGF (Vascular Endothelial Growth Factor) is activated by shear stress
Essential for blood vessel formation and trabeculation (development of the ventricular muscle structure).
eNOS (Endothelial Nitric Oxide Synthase) is activated by shear stress
This enzyme helps regulate blood vessel function by producing nitric oxide, which controls vessel dilation and blood pressure.
